CN101768086A - Amino methanol derivant and salt compound thereof as well as synthesizing method and medical application thereof - Google Patents

Amino methanol derivant and salt compound thereof as well as synthesizing method and medical application thereof Download PDF

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CN101768086A
CN101768086A CN200810051687A CN200810051687A CN101768086A CN 101768086 A CN101768086 A CN 101768086A CN 200810051687 A CN200810051687 A CN 200810051687A CN 200810051687 A CN200810051687 A CN 200810051687A CN 101768086 A CN101768086 A CN 101768086A
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arh
phenoxy group
tetrahydrochysene
benzyloxy
naphthalene
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CN101768086B (en
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王恩思
梁铁
路海滨
米浩宇
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Beijing Foreland Biopharma Co., Ltd.
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BEIJING FUKA BIOLOGICAL TECHNOLOGY CO LTD
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Priority to PCT/CN2009/001438 priority patent/WO2010078711A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/38—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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Abstract

The invention relates to an amino methanol derivant and a salt compound thereof as well as a synthesizing method and medical application thereof, belonging to the field of medicines. The medical application is applied in preparing immunosuppressive drugs and drugs for treating transplant rejection, immune and inflammatory diseases, multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis. The amino methanol derivant and a physiological salt thereof only act on S1P1, downwards regulate the S1P1 expression and suppress lymphocytes from entering peripheral blood circulation.

Description

Amino methanol derivant and salt compounds thereof and synthetic method thereof and its pharmaceutical use
Technical field
The invention belongs to field of medicaments, can be used for treating various graft-rejections and immune inflammation disease such as multiple sclerosis, systemic lupus erythematous, rheumatoid arthritis etc.
Background technology
Immunity system is the defensive structure of body protective self; mainly form, also comprise plasmocyte and mastocyte in other white corpuscle and reticular tissue in the blood by everywhere lymphocyte of lymphoid organ (thymus gland, lymphoglandula, spleen, tonsilla), other intraorganic Lymphoid tissue and whole body, antigen presenting cell etc.Constituting immune nucleus is lymphocyte, and it makes immunity system possess recognition capability and memory capability.Lymphocyte is traveled round whole body through blood and lymph, and lymphoid organ from one or Lymphoid tissue make dispersion lymphoid organ and Lymphoid tissue everywhere be linked to be a function integral body to the lymphoid organ or the Lymphoid tissue at another place.T cell and B cell are the most important immunocytes of human body.Each component function of immunity system normally be to keep the metastable assurance of body's immunity, the hyperfunction of the defective of any component or function all can be brought infringement to body.
Each component of immunity system blazons whole body, and is intricate, and particularly immunocyte and immune molecule constantly produce in body, circulate and upgrade.Immunity system has the ability to see things in their true light of height, can accurately discern own and non-own material, to keep the relative stability of body; Can also accept simultaneously, transmit, enlarge, store relevant immune information, reply and constantly adjust its responsiveness at immunologic information generation positive and negative with memory.Yet the imbalance of function of immune system also can be totally unfavorable to human body: the unusual easy generation that causes allergic phenomena of the recognition capability of human body, on the contrary can cause repeated infection; The Selfstabilizing ability of human body is unusual, and immunity system is reacted to the cell of self, causes autoimmune disease.
Immunosuppressor is the new medicament classification that a class grows up on multi-disciplinary research bases such as chemotherapy of tumors, organ transplantation, immunopathology and clinical immunology, has immunosuppressive action, can suppress the unusual immune response of body, be widely used in the treatment of anti-rejection of organ transplantation and autoimmune disorder at present.
Endoxan (CTX) is applied to clinical the earliest, it is found that afterwards that it in vivo can be by the hepatocyte microsome hydroxylation, and generation has the meta-bolites of alkanisation and has strong and persistent immunization.It influences each stage in the immunologic process by killing and wounding immunocyte, is used for nephrotic syndrome, systemic lupus erythematous, rheumatoid arthritis etc. as a kind of immunosuppressor.Than significant side effects its application is restricted.
Glucocorticosteroid nowadays be clinical in the most frequently used immunosuppressor, it can be by suppressing the phagocytic function of scavenger cell, minimizing generates and the immune response of inhibition human body at the autoantibody of autoantigen, is widely used in the rejection of serious acute infection, anaphylactic disease, histoorgan transplanting and treats some autoimmune disorder etc.
Azathioprine has the effect that suppresses T lymphocyte and bone-marrow-derived lymphocyte, is a kind of immunosuppressor, for many years, has become the active drug that prevents organ transplant rejection, and has been widely used in the treatment of various autoimmune disease.
Ciclosporin A (CsA) is as the cytokine synthetic inhibitor, and the cytokine gene of suppressor T cell is transcribed, and blocking t cell produces, and disturbs the T cell activation.It activates at G0/G1 phase (G0, G1, S are the different stepss in the thin chest mitotic cycle) intersection blocking t cell, belongs to the early stage activated inhibitor of T cell.From the eighties in 20th century, CsA is promoted the use of the transplanting of various organs and tissue successively, has obtained extensive success, has opened up the New Times of organ transplantation.
FK506 is the another kind of close immunoconjugator of exploitation after CsA, and it can prevent multiple transplant rejection, is applicable to liver transplantation especially.The immunosuppressive action of FK506 is about 10～100 times of CsA, and its acute and chronic rejection rate is low, and infection rate is low, hormone dosage is less, can reverse acute rejection, untoward reaction is few than CsA, so be expected to replace the immunosuppressor that CsA becomes organ transplantation postoperative first-selection.
(Rapamycin RPM) is used to resisting transplant rejection to rapamycin first, and it can effectively prevent rejection, share with other medicines, and the acute cellular rejection rate is descended.But kinase whose phosphorylation of its specificity arrestin and active protein and the DNA that suppresses cytokine induction thereof synthesize.Be T cell and B cell-stimulating activation inhibitor in late period.Rapamycin is as a kind of neotype immunosuppressant, and the inhibition immunocyte is not only in its effect, and suppresses the vascular smooth muscle hyperplasia and divide a word with a hyphen at the end of a line, and alleviates rejection.
Mycophenlate mofetil is by drugs approved by FDA, and is applied to clinically rapidly, and its curative effect height has very high selectively acting to the lymphocyte of propagation, simultaneously can also be by directly suppressing B cell proliferation, the formation of prevention antibody.
Above-mentioned immunosuppressor is because selectivity and specific restriction, in treatment, can damage patient's immune protection capability inevitably, cause patient's anti-infection ability to descend, the danger of malignant change increases, damage hematopoiesis, immunity system and liver, kidney, tract function, cause nerve and endocrine dysfunction, and cause some anaphylaxis etc.Can cause patient's alopecia as endoxan, cause hemorrhagic cystitis, as frequent micturition, odynuria, blood urine, proteinuria etc.; Glucocorticosteroid can increase the weight of or bring out infection, brings out stomach ulcer, merges hemorrhage and perforation, causes metabolism disorder, and rising blood pressure, blood sugar, blood fat cause osteoporosis, untoward reactions such as stimulating central nervous system system induced insomnia; Azathioprine can cause cholestasis and hepatocellular damage; MTX has digestive tube infringement symptom, as stomatocace, bloody stool etc., but still teratogenesis tire, stillborn foetus; Ciclosporin has kidney, liver and neural system toxicity, and can cause hypertension, the generation of secondary infection and tumour; FK506 also has renal toxicity, and also is far more than CsA aspect neurotoxicity, and pancreas islet β 2 cells are had damage, brings out diabetes; Rapamycin can cause white corpuscle, thrombopenia and hyperlipidaemia; Gastrointestinal symptoms such as mycophenolic acid fat then can cause vomiting, diarrhoea, leukopenia, septicemia and high blood uric acid, hyperkalemia, myalgia or drowsiness etc.
1-phosphoric acid-sheath ammonia enzyme acceptor antagonist FTY720 and sphingosine (a kind of endogenous lysolipin) have some structural similarities.Sphingosine forms 1-phosphoric acid-sheath ammonia enzyme, the part of the same clan of its receptor family via the phosphorylation of sphingosine enzyme induction.The activation of its acceptor causes following physiological activity: cytodifferentiation, existence and growth, and can play the adjustment etc. of the cytoskeleton reorganization that cell adhesion and cellular form change.In normal immune response, T lymphocyte and bone-marrow-derived lymphocyte are bred in lymphoglandula.When they were in the lymphoglandula, they were turned down 1-phosphoric acid-sheath ammonia enzyme acceptor and express.In case their activation and propagation are done, will heighten cell surface 1-phosphoric acid-sheath ammonia enzyme acceptor quantity, can make them leave lymphoglandula like this.Lymphocyte 1-phosphoric acid-sheath ammonia enzyme acceptor can combine with its part, therefore reduces 1-phosphoric acid-sheath ammonia enzyme.Lymphocyte no longer has the function that breaks away from the lymphoglandula then, and adheres in the lymphoglandula (1,2,3).The mechanism of action of tradition immunosuppressive drug such as ciclosporin is to suppress T lymphocyte and bone-marrow-derived lymphocyte activation.And 1-phosphoric acid-sheath ammonia enzyme acceptor antagonist is not to make the impaired mode of whole immune response by the deactivation lymphocyte, but achieves the goal by the method for restriction lymphocyte in lymphsystem.1-phosphoric acid-sheath ammonia enzyme acceptor antagonist can be used for treating various graft-rejections and immune inflammation disease.
1-phosphoric acid-sheath ammonia enzyme acceptor antagonist FTY720 is succeeded in developing by Novartis (Novartis Co.,Ltd), and has carried out clinical trial (4,5) relevant for multiple sclerosis and transplant patient at US and European, and tests by the clinical II phase.Yet FTY720 not only acts on 1-phosphoric acid-sheath ammonia enzyme acceptor-1 (S1P1), and acts on 1-phosphoric acid-sheath ammonia enzyme acceptor-3 (S1P3), therefore can cause side effects (6) such as bradycardia.This similar medicine does not still have the report of research and exploitation in China.
Summary of the invention
The invention provides a kind of immunosuppressive drug amino methanol derivant and salt compounds and synthetic method thereof.
The present invention relates to formula I compound:
Figure G2008100516876D0000031
Wherein:
X=methylene radical, oxygen
n＝1、2
The R1=methyl, chlorine, bromine, fluorine
R2=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
R3=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
The R4=methyl, chlorine, bromine, fluorine
And acceptable salt on the physiology.
One embodiment of the present invention, suc as formula the II compound:
Wherein:
The R1=methyl, chlorine, bromine, fluorine;
R2=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
R3=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
The R4=methyl, chlorine, bromine, fluorine;
And acceptable salt on the physiology.
One embodiment of the present invention is amino methanol derivant and salt compounds thereof, is hydrochloride compound.
The preparation method of amino methanol derivant is among the present invention, comprises according to following reaction formula and step:
Figure G2008100516876D0000051
Get 1 times of amount of (5,6,7,8 bit strips are substituent)-2-Tetralone an intermediate of Sertraline, 1.1 times of amounts of potassium cyanide, 9 times of amounts of volatile salt, 50% ethanolic soln is an amount of, heating reflux reaction 2h, ethanol steams and removes, and filters, and filter cake is washed to neutrality, dry (5 ', 6 ', 7 ', 8 ' bit strip is substituent)-3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone;
Get (5 ', 6 ', 7 ', 8 ' bit strip is substituent)-3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,1 times of amount of 5-diketone, alkaline solution is excessive greatly, heating reflux reaction, transfer pH=6 with HCl, filter, the washing filter cake is extremely neutral, dry (5,6,7,8 bit strips are substituent)-2-amino-1,2,3, the 4-tetrahydrochysene-2-naphthoic acid of getting;
Get (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-1 times of amount of 2-naphthoic acid, 3 times of amounts of lithium aluminum hydride, tetrahydrofuran (THF) is an amount of, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol.
The preparation method of amino methanol derivant hydrochloride compound of the present invention is:
Figure G2008100516876D0000061
The crude product compound of obtaining (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product compound directly carries out next step reaction without separating: it is an amount of to add methyl alcohol, concentrated hydrochloric acid is measured in above-mentioned crude product for 1 times, stirring at room reaction 0.5h, the solid that added diethyl ether is separated out, filter dry white solid (5,6,7,8 bit strips are substituent) 2-amino-1,2,3, the 4-tetrahydrochysene-2-naphthalene methylate hydrochlorate of getting.
The application in the preparation immunosuppressive drug of amino methanol derivant of the present invention and salt compounds thereof.
The application in the medicine of preparation treatment graft-rejection of amino methanol derivant of the present invention and salt compounds thereof.
The application in the medicine of preparation treatment immune inflammation disease of amino methanol derivant of the present invention and salt compounds thereof.
The application in the medicine of preparation treatment multiple sclerosis, systemic lupus erythematous, rheumatoid arthritis of amino methanol derivant of the present invention and salt compounds thereof.
The preferred salt compounds of the present invention is:
2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-5-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-n-octyl-8-chloro-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride 0 thereof
2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-7-n-hexyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
2-amino-6-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
(-)-2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate;
(+)-2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate;
(+)-2-amino-6-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate;
(-)-2-amino-6-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate;
(+)-2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate;
(-)-2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate;
(+)-2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate;
(-)-2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate;
Since water-soluble higher, compare with raw material or basic compound, and pharmacy acceptable salt is particularly suitable for medical applications.These salt must have pharmaceutically acceptable negatively charged ion or positively charged ion.The pharmaceutically-acceptable acid addition that is fit to according to compound of the present invention is the salt of mineral acid, acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid for example, with organic acid salt, acid is acetate, Phenylsulfonic acid, phenylformic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, oxyacetic acid, isethionic acid, lactic acid, lactobionic acid, toxilic acid, oxysuccinic acid, methylsulfonic acid, succsinic acid, right-toluenesulphonic acids, tartrate and trifluoroacetic acid for example.For medical purpose, chloride salt is particularly preferred.The pharmaceutically acceptable subsalt that is fit to is by salt, an alkali metal salt (for example sodium salt and sylvite) and alkaline earth salt (for example magnesium salts and calcium salt).
Have pharmaceutically unacceptable anionic salt and comprise equally within the scope of the invention, they can be used for preparation or purifying pharmacy acceptable salt and/or are used for non-treatment using for example external application as useful as intermediates.
Terminology used here " physiological functional deriv " relates to according to acceptable derivates on any physiology of formula 1 compound of the present invention, ester for example, in case they are to Mammals, for example people administration, can (directly or indirectly) production I compound or its active metabolite.Physiological functional deriv also comprises the prodrug according to compound of the present invention.This class prodrug can internal metabolism be according to compound of the present invention.These prodrugs itself can be active or non-activities.
Can also there be various polymorphics according to compound of the present invention, for example amorphous and crystallinity polymorphic.All polymorphics according to compound of the present invention all comprise within the scope of the invention, are further aspects of the present invention.
Below, all appellations to " according to the compound of formula (I) " all relate to salt, solvate and the physiological functional deriv of aforesaid formula (I) compound and as described herein they.
Compound according to formula (I) depends on a large amount of factors, for example selected particular compound, desired use, administering mode and patient's clinical condition for reaching the necessary amount of required biology effect.In general, every day, dosage was at 20mg to 200mg, usually from 20mg to 50mg.About the prevention or the treatment of above-mentioned disease, can use compound itself according to the compound of formula (I), but preferably use the pharmaceutical compositions with the vehicle that can tolerate.Vehicle is compatible with other compositions of composition and must tolerate certainly on the harmless meaning patient health.Vehicle can be solid or liquid, and perhaps the two all is, preferably is mixed with single dose with compound, and for example tablet wherein can contain 0.05 to 95 weight % active compound.Can also there be other pharmaceutically active substances, comprise other compounds according to formula (I).Can prepare by one of known method of pharmacy according to pharmaceutical composition of the present invention.These methods are formed with pharmaceutically acceptable vehicle and/or auxiliary agent by mixing each component in essence.
Pharmaceutical composition according to the present invention is to be fit to those of oral, rectum, part, stop talking (for example hypogloeeis) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenously) administration, but optimal administering mode depends on the character of the character of the disease for the treatment of in each case and seriousness and used compound according to formula (I) under every kind of particular case.Sugar-coated preparation and sugar-coat sustained release preparation are also included within the scope of the present invention.The preparation of acid proof and enteric is preferred.The enteric coating that is fit to comprises the anionic polymer of rhodia phthalic ester, acetate polyethylene phthalic ester, hydroxypropylmethylcellulose phthalate and methylacrylic acid and methyl methacrylate.
The medical compounds that is fit to oral administration can be unit independently, for example capsule, cachet, plating agent or tablet, and they contain a certain amount of compound according to formula (I) separately; Pulvis or granule; Solution in moisture or anhydrous liq or suspension; Oil-in-water-type or water-in-oil emulsion.Mention, these compositions can be by the method for pharmacy preparation that is fit to arbitrarily, and this method comprises the step that active compound and vehicle (can by one or more other become to be grouped into) be come in contact.In general, composition is preparation like this, and the solid excipient of uniformity ground mixed active compound and liquid and/or fine pulverizing then if necessary, makes the product moulding.Thereby tablet for example can prepare like this, the compacting compound: if suitably, with the powder or the particle of one or more other compositions or make its moulding.Compressed tablet can prepare like this, in the machinery that is fit to, with the compound of free-flowing form, for example powder or particle form, if suitably, mix with tackiness agent, lubricant, inert diluent and/or a kind of (in a large number) surfactant/dispersant earlier, compacting in flakes.Matrix band can prepare like this, in the machinery that is fit to, uses the moistening powder compound moulding of inert liquid diluent.
The pharmaceutical composition that is fit to per os (hypogloeeis) administration comprises lozenge, it contains the compound and the correctives of with good grounds formula (I), is sucrose and gum arabic traditionally, and pastille, it comprises compound in inert base, the former is gelatin and glycerine or sucrose and gum arabic for example.
The pharmaceutical composition that is fit to administered parenterally preferably includes the sterile aqueous preparations according to the compound of formula (I), and they are isoosmotic with the expection person's that is subjected to the medicine blood preferably.These preparations are intravenous administration preferably, but that administration also can take is subcutaneous, the mode of intramuscular or intradermal injection.These preparations can preferably prepare like this, mixing cpd and water, and it is aseptic and ooze with blood etc. to give gained solution.Generally contain 0.1 to 5 weight % active compound according to Injectable composition of the present invention.
The pharmaceutical composition of suitable rectal administration is the suppository of single dose preferably.They can prepare like this, mix compound and one or more conventional solid excipients according to formula (I), and for example theobroma oil makes the gained mixture forming.
Be fit to the pharmaceutical composition of local skin medication preferably ointment, creme, paste, sprays, aerosol or finish.Operable vehicle is the combination of mineral jelly, lanolin, polyoxyethylene glycol, alcohols and two or more these materials.The concentration of active compound generally accounts for 0.1 to 15% of composition weight.
Transdermal administration also is possible.The pharmaceutical composition that is fit to transdermal administration can be single patch, and they are fit to closely contact for a long time with patient's epidermis.This class patch is fit to contain the optional aqueous solution that is cushioned of active compound, compound dissolution and/or be dispersed in the tackiness agent or be dispersed in the polymkeric substance.The activity compound concentration that is fit to is about 1% to 35%, preferably from about 3% to 15%.Possible especially is.Active compound can for example be described in Pharmaceutical Research (study of pharmacy), 2 (6): 318 (1986) by electron transport or from being released in electric osmose.
The compounds of this invention and physiological salt thereof only act on S1P1, and downward modulation S1P1 expresses, and suppress lymphocyte and enter peripheral blood circulation.Be used for the treatment of various graft-rejections and immune inflammation disease such as multiple sclerosis, systemic lupus erythematous, rheumatoid arthritis etc.
Embodiment
The present invention relates to formula I compound:
Figure G2008100516876D0000101
Wherein:
X=methylene radical, oxygen
n＝1、2
The R1=methyl, chlorine, bromine, fluorine
R2=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
R3=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
The R4=methyl, chlorine, bromine, fluorine
And acceptable salt on the physiology.
One embodiment of the present invention, suc as formula the II compound:
Figure G2008100516876D0000111
Wherein:
The R1=methyl, chlorine, bromine, fluorine;
R2=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
R3=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
The R4=methyl, chlorine, bromine, fluorine;
And acceptable salt on the physiology.
One embodiment of the present invention is amino methanol derivant and salt compounds thereof, is hydrochloride compound.
The preparation method of amino methanol derivant is among the present invention, comprises according to following reaction formula and step:
Get 1 times of amount of (5,6,7,8 bit strips are substituent)-2-Tetralone an intermediate of Sertraline, 1.1 times of amounts of potassium cyanide, 9 times of amounts of volatile salt, 50% ethanolic soln is an amount of, heating reflux reaction 2h, ethanol steams and removes, and filters, and filter cake is washed to neutrality, dry (5 ', 6 ', 7 ', 8 ' bit strip is substituent)-3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone;
Get (5 ', 6 ', 7 ', 8 ' bit strip is substituent)-3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,1 times of amount of 5-diketone, alkaline solution is excessive greatly, heating reflux reaction, transfer pH=6 with HCl, filter, the washing filter cake is extremely neutral, dry (5,6,7,8 bit strips are substituent)-2-amino-1,2,3, the 4-tetrahydrochysene-2-naphthoic acid of getting;
Get (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-1 times of amount of 2-naphthoic acid, 3 times of amounts of lithium aluminum hydride, tetrahydrofuran (THF) is an amount of, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol.
The preparation method of amino methanol derivant hydrochloride compound of the present invention is:
Figure G2008100516876D0000131
The crude product compound of obtaining (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product compound directly carries out next step reaction without separating: it is an amount of to add methyl alcohol, concentrated hydrochloric acid is measured in above-mentioned crude product for 1 times, stirring at room reaction 0.5h, the solid that added diethyl ether is separated out, filter dry white solid (5,6,7,8 bit strips are substituent) 2-amino-1,2,3, the 4-tetrahydrochysene-2-naphthalene methylate hydrochlorate of getting.
Embodiment 1
The synthetic method of 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-001) and hydrochloride (FC-002) (hereinafter to be referred as FC-001, FC-002) thereof is as follows:
Figure G2008100516876D0000132
3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Get 2-Tetralone an intermediate of Sertraline 8g (54.8mmol), potassium cyanide 4g (61.5mmol), volatile salt 48g (500mmol), 50% ethanolic soln 320mL, heating reflux reaction 2h, ethanol steams and removes, and filters, filter cake is washed to neutrality, dry white solid 3 ', the 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2 that gets, 5-diketone 8.6g, productive rate 73%; Mp 150-152 ℃; 1H NMR (400MHz, DMSO) δ: 10.69 (s, 1H ,-NH-), 8.29 (s, 1H ,-NH-), 7.08-7.13 (m, 4H, 4 *-ArH), 3.12 (d, 1H, J=17.2Hz ,-CH-), 2.88-2.97 (m, 2H ,-CH 2-), 2.76 (d, 1H, J=16.8Hz), 1.94-1.98 (m, 1H ,-CH-), 1.82-1.84 (m, 1H ,-CH-); 13C NMR (100MHz, DMSO) δ: 178.1,156.3,134.8,132.6,128.9,128.5,125.9,125.8,60.7,36.8,30.3,24.7.
Synthesizing of 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Get 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 8g (37.0mmol), hydrated barta 63g (370mmol), water 500mL, heating reflux reaction 36h transfers pH value of solution=6 with 10%HCl, filter, the washing filter cake is extremely neutral, dry white solid 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid 6.5g, the productive rate 93% of getting; Mp258-260 ℃; 1H NMR (400MHz, DMSO) δ: 7.5 (brs, 2H ,-NH 2), 7.04-7.10 (m, 4H, 4 *-ArH), 3.20-3.32 (m, 3H ,-COOH ,-CH 2-), 2.82-2.84 (m, 1H ,-CH-), 2.71-2.79 (m, 1H ,-CH-), 2.07-2.10 (m, 1H ,-CH-), 1.82-1.85 (m, 1H ,-CH-); 13C NMR (100MHz, DMSO) δ: 172.0,135.2,133.9,128.8,128.4,125.6,125.4,58.1,35.7,29.4,24.9.
Synthesizing of 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-001) and hydrochloride (FC-002) thereof
Get 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid 0.5g (2.6mmol), lithium aluminum hydride 0.3g (7.8mmol), tetrahydrofuran (THF) 20mL, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the solid that added diethyl ether is separated out, and filters, dry white solid 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.33g, the productive rate 60% of getting; Mp 174-176 ℃; 1H NMR (400MHz, DMSO) δ: 8.17 (s, 3H ,-NH 3 +), 7.12-7.12 (m, 4H, 4 *-ArH), 5.55 (t, 1H, J=4.8Hz ,-OH), 3.44 (d, 2H, J=4.8Hz ,-CH 2-), 2.91 (s, 2H ,-CH 2-), 2.80-2.80 (m, 2H ,-CH 2-), 1.94-1.95 (m, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 134.5,132.4,129.1,128.5,126.1,125.9,62.7,55.7,34.0,27.2,24.7; Mass spectrum ESI-MS:(C 11H 15NO.HCl) (M ++ 1) 177; Infrared spectra IR (KBr) v cm -1: 3267,2921,2645,2539,2034,1714,1602,1497,1453,1326,1062,763,739.
The method for splitting of FC-002 is as follows:
Figure G2008100516876D0000151
Get racemic mixture [(±) FC-001] 2g (11.3mmol), R-(-)-amygdalic acid 2g (13.2mmol), methyl alcohol 20mL, stirring at room reaction 0.5h, methyl alcohol revolves and removes, the adularescent solid that adds diethyl ether is separated out, and filters, dry R-(-)-mandelate 3.5g that gets crude product levorotatory compound [(-)-FC-001]; This crude product with (methyl alcohol: mixed solvent recrystallization ether=2: 3) 5 times, R-(-)-mandelate 0.8g of elaboration left handed crystal compound [(-)-FC-001], [α] D 20=-43.08 ° (c=1.0, methyl alcohol), mother liquor be spin-dried for R-(-)-mandelate 0.7g of elaboration dextrorotation solid chemical compound [(+)-FC-001], [α] D 20=-38.05 ° (c=1.0, methyl alcohol); R-(-)-mandelate of best quality compound [(-)-FC-001] and R-(-)-mandelate of [(+)-FC-001] are added 10% aqueous sodium hydroxide solution 10mL respectively, stirring at room reaction 0.5h, extracted with diethyl ether, organic phase be spin-dried for elaboration levorotatory compound [(-)-FC-001] 0.4g, [α] D 20=-0.9 ° (c=1.0, methyl alcohol) and elaboration dextrorotatory compound [(+)-FC-001] 0.4g[α] D 20=+0.9 ° (c=1.0, methyl alcohol); Elaboration levorotatory compound [(-)-FC-001] and dextrorotatory compound [(+)-FC-001] are added methyl alcohol 5mL respectively, concentrated hydrochloric acid 0.1mL, stirring at room reaction 0.5h, the adularescent solid that adds diethyl ether is separated out, filter, drying gets levorotatory compound [(-)-FC-002] 0.5g, [α] respectively D 20=-1.2 ° (c=1.0, methyl alcohol) and dextrorotatory compound [(+)-FC-002] 0.4g, [α] D 20=+1.1 ° (c=1.0, methyl alcohol).
Embodiment 2:
The synthetic method of 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-003) and hydrochloride (FC-004) (hereinafter to be referred as FC-003, FC-004) thereof is as follows:
Figure G2008100516876D0000161
Synthesizing of 7-bromo-2-Tetralone an intermediate of Sertraline
Between getting-bromo-acid 20g (94mmol), 1,2-ethylene dichloride 240mL, thionyl chloride 21mL (296mmol), heating reflux reaction 4h is spin-dried for solvent, 100mL adds methylene chloride, above-mentioned solution of acid chloride is added in the mixing solutions of the 300mL methylene dichloride that contains aluminum trichloride (anhydrous) 28g (209mmol), is being lower than 0 ℃ of feeding ethylene reaction down, question response finishes back (approximately 4h), add water 200mL, dichloromethane extraction, organic phase are used 1N HCl successively, the saturated sodium carbonate solution washing, anhydrous magnesium sulfate drying, steaming desolventizes silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 5), get white solid 7-bromo-2-Tetralone an intermediate of Sertraline 10g, productive rate 50%; Mp 72-74 ℃; 1H NMR (400MHz, CDCl 3) δ: 7.33 (d, 1H, J=8.0Hz ,-ArH), 7.28 (s, 1H ,-ArH), 7.10 (d, 1H, J=8.0Hz ,-ArH), 3.56 (s, 2H ,-CH 2-), 3.02 (t, 2H, J=8.0Hz ,-CH 2-), 2.54 (t, 2H, J=8.0Hz ,-CH 2-); 13C NMR (100MHz, CDCl 3) δ: 209.0,135.5,135.4,130.8,129.7,129.1,120.7,44.4,37.7,27.7.
Synthesizing of 7-normal-butyl-2-Tetralone an intermediate of Sertraline
Get 7-bromo-2-Tetralone an intermediate of Sertraline 10g (44.4mmol), normal butane ylboronic acid 6g (58.8mmol), three water potassiumphosphate 42g (157.9mmol), palladium 0.5g (2.2mmol), thricyclohexyl phosphorus 1.25g (4.4mmol), toluene 200mL, water 10mL, heating reflux reaction 1.5h under nitrogen protection, cooling, add water 200mL, dichloromethane extraction, the organic phase anhydrous sodium sulfate drying, steaming desolventizes silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 5), get white solid 7-butyl-2-Tetralone an intermediate of Sertraline 7.5g, productive rate 80%; Mp 60-62 ℃; 1H NMR (400MHz, CDCl 3) δ: 7.14 (d, 1H, J=8.0Hz ,-ArH), 7.03 (d, 1H, J=8.0Hz ,-ArH), 6.94 (s, 1H ,-ArH), 3.56 (s, 2H ,-CH 2-), 3.03 (t, 2H, J=8.0Hz ,-CH 2-), 2.56-2.56 (m, 4H, 2 *-CH 2-), 1.54-1.54 (m, 2H ,-CH 2-), 1.32-1.38 (m, 2H ,-CH 2-), 0.93 (t, 3H, J=7.2Hz ,-CH 3); 13C NMR (100MHz, CDCl 3) δ: 210.7,141.5,133.7,133.0,128.1,127.4,126.7,44.9,38.3,35.1,33.6,27.8,22.3,13.8.3 ', 4 '-dihydro-7 '-normal-butyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-normal-butyl-3,4-dialin-2-ketone 5.5g (27.2mmol), potassium cyanide 1.95g (30.0mmol), volatile salt 24g (250mmol), 50% ethanolic soln 160mL, get white solid 3 ', 4 '-dihydro-7 '-normal-butyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 5.1g, productive rate 69%;
mp?211-213℃； 1H?NMR(400MHz，DMSO)δ：10.67(s，1H，-NH-)，8.27(s，1H，-NH-)，7.02(d，1H，J＝8.0Hz，-ArH)，6.95(d，1H，J＝8.0Hz，-ArH)，6.90(s，1H，-ArH)，3.01(d，1H，J＝16.8Hz，-CH-)，2.84-2.88(m，2H，-CH 2-)，2.72(d，1H，J＝16.8Hz，-CH-)，2.47-2.47(m，2H，-CH 2-)，1.91-1.96(m，1H，-CH-)，1.77-1.80(m，1H，-CH-)，1.49-1.55(m，2H，-CH 2-)，1.25-1.34(m，2H，-CH 2-)，0.89(t，3H，J＝7.6Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：178.2，156.2，139.7，132.3，131.9，128.6，128.4，126.0，60.8，36.8，34.4，33.2，30.1，24.3，21.7，13.7。
Synthesizing of 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-normal-butyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 1.5g (5.5mmol), hydrated barta 9.5g (55mmol), water 50mL, get white solid 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 1.0g, productive rate 77%;
mp?228-230℃； 1H?NMR(400MHz，DMSO)δ：7.09(brs，3H，-COOH，-NH 2)，6.98(d，1H，J＝7.6Hz，-ArH)，6.90(d，1H，J＝7.6Hz，-ArH)，6.87(s，1H，-ArH)，3.30-3.43(m，2H，-CH 2-)，2.70-2.75(m，2H，-CH 2-)，2.47-2.50(m，2H，-CH 2-)，2.04-2.08(m，1H，-CH-)，1.78-1.80(m，1H，-CH-)，1.52-1.55(m，2H，-CH 2-)，1.30-1.33(m，2H，-CH 2-)，0.88(t，3H，J＝7.2Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：172.0，139.6，133.5，132.3，128.6，128.3，125.6，58.2，35.8，34.4，33.2，29.4，24.4，21.7，13.7。
Synthesizing of 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 1.0g (4.0mmol), lithium aluminum hydride 0.45g (12.0mmol), tetrahydrofuran (THF) 20mL, stirring at room reaction 12h adds water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the solid that added diethyl ether is separated out, and filters, dry white solid 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 50% of getting;
Mp 187-189 ℃; 1H NMR (400MHz, DMSO) δ: 8.13 (s, 3H ,-NH 3 +), 7.14 (d, 1H, J=8.0Hz ,-ArH), 6.95 (d, 1H, J=7.6Hz ,-ArH), 6.90 (s, 1H ,-ArH), 5.52 (s, 1H ,-OH), 3.43 (s, 2H ,-CH 2-), 2.87 (s, 2H ,-CH 2-), 2.72-2.77 (m, 2H ,-CH 2-), 2.47-2.51 (m, 2H ,-CH 2-), 1.89-1.93 (m, 2H ,-CH 2-), 1.50-1.55 (m, 2H ,-CH 2-), 1.30-1.33 (m, 2H ,-CH 2-), 0.88 (t, 3H, J=7.2Hz ,-CH 3); 13CNMR (100MHz, DMSO) δ: 139.9,132.2,131.6,128.8,128.4,126.2,62.8,55.8,34.3,34.1,33.1,27.4,24.3,21.7,13.7; Mass spectrum ESI-MS:(C 15H 23NO.HCl) (M ++ 1) 233; Infrared spectra IR (KBr) v cm -1: 3380,2956,2928,2640,2541,2019,1603,1506,1466,1442,1063,818.
The method for splitting of FC-004 is as follows:
Get racemic mixture [(±) FC-003] 2g (8.6mmol), S-(+)-amygdalic acid 1.6g (10.3mmol), methyl alcohol 20mL, stirring at room reaction 0.5h, methyl alcohol revolves and removes, the adularescent solid that adds diethyl ether is separated out, and filters, dry S-(+)-mandelate 3.0g that gets crude product levorotatory compound [(-)-FC-003]; This crude product with (methyl alcohol: mixed solvent recrystallization ether=2: 3) 5 times, S-(+)-mandelate 0.8g of elaboration left handed crystal compound [(-)-FC-003], [α] D 20=+39.04 ° (c=1.0, methyl alcohol), mother liquor be spin-dried for S-(+)-mandelate 0.7g of elaboration dextrorotation solid chemical compound [(+)-FC-003], [α] D 20=+36.20 ° (c=1.0, methyl alcohol); S-(+)-mandelate of best quality compound [(-)-FC-003] and S-(+)-mandelate of [(+)-FC-003] are added 10% aqueous sodium hydroxide solution 10mL respectively, stirring at room reaction 0.5h, extracted with diethyl ether, organic phase evaporate to dryness get elaboration levorotatory compound [(-)-FC-003] 0.4g, [α] D 20=-0.9 ° (c=1.0, methyl alcohol) and elaboration dextrorotatory compound [(+)-FC-003] 0.4g, [α] D 20=+1.2 ° (c=1.0, methyl alcohol); Elaboration levorotatory compound [(-)-FC-003] and dextrorotatory compound [(+)-FC-003] are added methyl alcohol 5mL respectively, concentrated hydrochloric acid 0.1mL, stirring at room reaction 0.5h, the adularescent solid that adds diethyl ether is separated out, filter, drying gets levorotatory compound [(-)-FC-004] 0.4g, [α] respectively D 20=-1.1 ° (c=1.0, methyl alcohol) and dextrorotatory compound [(+)-FC-004] 0.5g, [α] D 20=+1.2 ° (c=1.0, methyl alcohol).
Embodiment 3:
The synthetic method of 2-amino-5-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-005) and hydrochloride (FC-006) (hereinafter to be referred as FC-005, FC-006) thereof is as follows:
Synthesizing of 5-bromo-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-bromo-2-Tetralone an intermediate of Sertraline, between getting-bromo-acid 20g (94mmol), 1,2-ethylene dichloride 240mL, thionyl chloride 21mL (296mmol), methylene dichloride 500mL, aluminum trichloride (anhydrous) 28g (209mmol) gets white solid 5-bromo-2-Tetralone an intermediate of Sertraline 5g, productive rate 25%;
mp?76-78℃； 1H?NMR(400MHz，CDCl 3)δ：7.48(t，1H，J＝4.0Hz，-ArH)，7.02(t，2H，J＝4.0Hz，2×-ArH)，3.60(s，2H，-CH 2-)，3.24(t，2H，J＝8.0Hz，-CH 2-)，2.56(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：209.3，136.1，135.4，130.8，127.9，127.4，123.6，44.8，37.4，27.9。
Synthesizing of 5-normal-butyl-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-normal-butyl-2-Tetralone an intermediate of Sertraline, get 5-bromo-2-Tetralone an intermediate of Sertraline 10g (44.4mmol), normal butane ylboronic acid 6g (58.8mmol), three water potassiumphosphate 42g (157.9mmol), palladium 0.5g (2.2mmol), thricyclohexyl phosphorus 1.25g (4.4mmol), toluene 200mL, water 10mL gets white solid 5-normal-butyl-2-Tetralone an intermediate of Sertraline 7.5g, productive rate 80%;
mp?60-62℃； 1H?NMR(400MHz，CDCl 3)δ：7.14(t，1H，J＝7.6Hz，-ArH)，7.08(d，1H，J＝7.6Hz，-ArH)，6.97(d，1H，J＝7.6Hz，-ArH)，3.58(s，2H，-CH 2-)，3.06(t，2H，J＝6.8Hz，-CH 2-)，2.67(t，2H，J＝6.8Hz，-CH 2-)，2.52(t，2H，J＝6.8Hz，-CH 2-)，1.52-1.57(m，2H，-CH 2-)，1.40-1.44(m，2H，-CH 2-)，0.93(t，3H，J＝7.2Hz，-CH 3)； 13C?NMR(100MHz，CDCl 3)δ：210.8，139.8，134.7，133.6，127.8，126.6，45.6，37.9，33.2，33.1，29.6，24.1，22.6，13.9。
3 ', 4 '-dihydro-5 '-normal-butyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone is got 5-normal-butyl-2-Tetralone an intermediate of Sertraline 5.5g (27.2mmol), potassium cyanide 1.95g (30.0mmol), volatile salt 24g (250mmol), 50% ethanolic soln 160mL gets white solid 3 ', 4 '-dihydro-5 '-normal-butyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 5.1g, productive rate 69%;
mp?220-222℃； 1H?NMR(400MHz，DMSO)δ：10.67(s，1H，-NH-)，8.27(s，1H，-NH-)，7.05(t，1H，J＝8.0Hz，-ArH)，7.00(d，1H，J＝8.0Hz，-ArH)，6.91(d，1H，J＝8.0Hz，-ArH)，3.13(d，1H，J＝16.8Hz，-CH-)，2.89-2.890(m，2H，-CH 2-)，2.75(d，1H，J＝16.8Hz，-CH-)，2.50-2.54(m，2H，-CH 2-)，1.93-1.97(m，1H，-CH-)，1.83-1.86(m，1H，-CH-)，1.49-1.53(m，2H，-CH 2-)，1.34-1.38(m，2H，-CH 2-)，0.93(t，3H，J＝7.2Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：178.3，156.4，140.1，132.8，132.6，126.7，126.5，125.5，60.5，37.5，31.9，31.7，30.1，22.3，21.6，13.8。
Synthesizing of 2-amino-5-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get compound 3 ', 4 '-dihydro-5 '-normal-butyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 1.5g (5.5mmol), hydrated barta 9.5g (55mmol), water 50mL, get white solid 2-amino-5-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 1.0g, productive rate 77%;
mp?229-231℃； 1H?NMR(400MHz，DMSO)δ：7.03(t，1H，J＝7.2Hz，-ArH)，6.95(d，1H，J＝7.2Hz，-ArH)，6.88(d，1H，J＝7.2Hz，-ArH)，3.33(d，1H，J＝17.2Hz，-CH-)，2.77-2.780(m，1H，-CH-)，2.70(d，1H，J＝17.2Hz，-CH-)，2.64-2.66(m，1H，-CH-)，2.50-2.53(m，2H，-CH 2-)，2.06-2.09(m，1H，-CH-)，1.86-1.87(m，1H，-CH-)，1.47-1.50(m，2H，-CH 2-)，1.35-1.38(m，2H，-CH 2-)，0.92(t，3H，J＝7.2Hz，-CH 3)； 13C?NMR??(100MHz，DMSO)δ：172.1，139.9，133.7，133.1，126.7，126.1，125.3，57.7，36.4，31.9，31.8，29.4，22.2，21.6，13.8。
Synthesizing of 2-amino-5-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-5-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 1.0g (4.0mmol), lithium aluminum hydride 0.45g (12.0mmol), tetrahydrofuran (THF) 20mL, stirring at room reaction 12h adds water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-5-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the solid that added diethyl ether is separated out, and filters, dry white solid 2-amino-5-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 50% of getting;
Mp 190-192 ℃; 1H NMR (400MHz, DMSO) δ: 8.12 (brs, 3H ,-NH 3 +), 7.07 (t, 1H, J=7.2Hz ,-ArH), 7.00 (d, 1H, J=7.2Hz ,-ArH), 6.92 (d, 1H, J=7.2Hz ,-ArH), 5.52 (d, 1H, J=4.8Hz ,-OH), 3.43 (d, 2H, J=8.4Hz ,-CH 2-), 2.86 (s, 2H ,-CH 2-), 2.76-2.81 (m, 2H ,-CH 2-), 2.52-2.54 (m, 2H ,-CH 2-), 1.96-1.99 (m, 2H ,-CH 2-), 1.48-1.52 (m, 2H ,-CH 2-), 1.34-1.39 (m, 2H ,-CH 2-), 0.91 (t, 3H, J=7.2Hz ,-CH 3); 13C NMR (100MHz, DMSO) δ: 140.2,132.4,126.9,126.6,125.7,62.7,55.4,34.6,31.8,27.4,22.1,21.7,13.8; Mass spectrum ESI-MS:(C 15H 23NO.HCl) (M ++ 1) 233; Infrared spectra IR (KBr) v cm -1: 3409,3270,2956,2930,2872,2643,2554,2040,1597,1519,1466,1050.
Embodiment 4:
The synthetic method of 2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-007) and hydrochloride (FC-008) (hereinafter to be referred as FC-007, FC-008) thereof is as follows:
Figure G2008100516876D0000211
Synthesizing of 7-n-octyl-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-normal-butyl-2-Tetralone an intermediate of Sertraline, get 7-bromo-2-Tetralone an intermediate of Sertraline 5g (22.2mmol), octane ylboronic acid 5g (31.6mmol), three water potassiumphosphate 21g (78.9mmol), thricyclohexyl phosphorus 0.7g (2.5mmol), palladium 0.25g (1.1mmol), toluene 100mL, water 5mL gets faint yellow solid 7-n-octyl-2-Tetralone an intermediate of Sertraline 4.5g, productive rate 78%;
mp?72-74℃； 1H?NMR(400MHz，CDCl 3)δ：7.14(d，1H，J＝8.0Hz，-ArH)，7.03(d，1H，J＝8.0Hz，-ArH)，6.94(s，1H，-ArH)，3.56(s，2H，-CH 2-)，3.03(t，2H，J＝8.0Hz，-CH 2-)，2.56-2.59(m，4H，2×-CH 2-)，1.60-1.63(m，2H，-CH 2-)，1.27-1.30(m，10H，5×-CH 2-)，0.88(t，3H，J＝8.0Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：210.2，141.4，133.6，132.9，127.9，127.2，126.6，44.8，38.2，35.4，31.7，31.4，29.3，29.1，27.7，22.4，13.9。
3 ', 4 '-dihydro-7 '-n-octyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-n-octyl-2-Tetralone an intermediate of Sertraline 5g (19.4mmol), potassium cyanide 1.5g (23.1mmol), volatile salt 17.5g (182.3mmol), 50% ethanolic soln 125mL, get white solid 3 ', 4 '-dihydro-7 '-n-octyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 5.0g, productive rate 79%;
mp?267-269℃； 1H?NMR(400MHz，DMSO)δ：10.67(s，1H，-NH-)，8.27(s，1H，-NH-)，7.15(d，1H，J＝8.0Hz，-ArH)，6.94(d，1H，J＝8.0Hz，-ArH)，6.89(s，1H，-ArH)，3.07(d，1H，J＝16.8Hz，-CH-)，2.86-2.88(m，2H，-CH 2-)，2.72(d，1H，J＝16.8Hz，-CH-)，2.50-2.70(m，2H，-CH 2-)，1.90-1.92(m，1H，-CH-)，1.79-1.89(m，1H，-CH-)，1.50-1.52(m，2H，-CH 2-)，1.26-1.27(m，10H，5×-CH 2-)，0.85(t，3H，J＝7.2Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：178.2，156.3，139.8，132.3，131.9，128.6，126.0，60.8，36.8，34.7，31.2，31.1，30.1，28.8，28.7，28.6，24.3，22.4，13.9。
Synthesizing of 2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2 naphthoic acid
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7-n-octyl-spiral shell [tetrahydroglyoxaline-4,2 '-naphthalene]-2,5-diketone 1.5g (4.3mmol), hydrated barta 7.5g (43mmol), water 50mL, get white solid 2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2 naphthoic acid 1.0g, productive rate 77%;
mp?315-317℃； 1H?NMR(400MHz，DMSO)δ：8.30(brs，1H，-COOH)，7.02(d，1H，J＝8.0Hz，-ArH)，6.96(d，1H，J＝8.0Hz，-ArH)，6.89(s，1H，-ArH)，3.40(brs，2H，-NH 2)，3.28(d，1H，J＝16.8Hz，-CH-)，3.08(d，1H，J＝16.8Hz，-CH-)，2.77-2.81(m，2H，-CH 2-)，2.47-2.50(m，2H，-CH 2-)，2.15-2.17(m，2H，-CH 2-)，1.52-1.53(m，2H，-CH 2-)，1.26-1.27(m，10H，5×-CH 2-)，0.85(t，3H，J＝7.2Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：172.2，140.1，131.6，131.3，128.3，128.3，126.2，57.4，34.7，34.5，31.2，31.0，28.9，28.8，28.7，28.6，24.2，22.0，13.9。
Synthesizing of 2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2-naphthoic acid 1.0g (3.3mmol), lithium aluminum hydride 0.37g (10mmol), tetrahydrofuran (THF) 20mL, stirring at room reaction 12h adds water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the solid that added diethyl ether is separated out, and filters, dry white solid 2-amino-7-n-octylcyclam, 2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 50% of getting;
Mp 193-195 ℃; 1H NMR (400MHz, DMSO) δ: 8.15 (brs, 3H ,-NH 3 +), 7.01 (d, 1H, J=7.6Hz ,-ArH), 6.94 (d, 1H, J=7.6Hz ,-ArH), 6.90 (s, 1H ,-ArH), 5.54 (s, 1H ,-OH), 3.42 (s, 2H ,-CH 2-), 2.78 (s, 2H ,-CH 2-), 2.74-2.77 (m, 2H ,-CH 2-), 2.49-2.50 (m, 2H ,-CH 2-), 1.92-1.924 (m, 2H ,-CH 2-), 1.51-1.53 (m, 2H ,-CH 2-), 1.25-1.26 (m, 10H, 5 *-CH 2-), 0.85 (t, 3H, J=7.2Hz ,-CH 3); 13C NMR (100MHz, DMSO) δ: 139.9,132.1,131.6,128.8,128.4,126.3,62.8,55.8,34.7,34.1,31.3,31.0,28.8,28.7,28.6,27.4,24.3,22.1,13.9; Mass spectrum ESI-MS:(C 19H 31NO.HCl) (M ++ 1) 289; Infrared spectra IR (KBr) v cm -1: 3384,2956,2925,2854,2635,2001,1601,1505,1466,1061,819.
The method for splitting of FC-008 is as follows:
Experimentation is got racemic mixture [(±) FC-007] 3g (10.4mmol) with the fractionation of FC-007, S-(+)-amygdalic acid 1.9g (12.4mmol), and methyl alcohol 20mL gets levorotatory compound [(-)-FC-008] 0.4g, [α] D 20=-1.5 ° (c=1.0, methyl alcohol) and dextrorotatory compound [(+)-FC-008] 0.5g, [α] D 20=+1.7 ° (c=1.0, methyl alcohol).
Embodiment 5:
The synthetic method of 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-009) and hydrochloride (FC-010) (hereinafter to be referred as FC-009, FC-010) thereof is as follows:
Figure G2008100516876D0000241
Synthesizing of 4-oxygen base-toluylic acid in positive heptan
Get right-hydroxyl phenylacetic acid 5g (32.9mmol), positive heptyl bromide 11.7g (65.8mmol), salt of wormwood 9.0g (65.8mmol), ethanol 100mL, heating reflux reaction 3h, cooling, ethanol steams and removes, and adds water 200mL, ethyl acetate extraction, water layer is transferred pH=2 with concentrated hydrochloric acid, and ethyl acetate extraction merges organic phase, anhydrous magnesium sulfate drying, be spin-dried for solvent silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 5), get oily compound 4-oxygen in positive heptan base-toluylic acid 5.5g, productive rate 67%; 1H NMR (400MHz, DMSO) δ: 12.2 (s, 1H ,-COOH), 7.14 (d, 2H, J=8.0Hz, 2 *-ArH), 6.85 (d, 2H, J=8.0Hz, 2 *-ArH), 3.92 (t, 2H, J=8.0Hz ,-CH 2-O), 3.47 (s, 2H ,-CH 2-), 1.67-1.70 (m, 2H ,-CH 2-), 1.28-1.39 (m, 8H, 4 *-CH 2-), 0.87 (t, 3H, J=6.8Hz ,-CH 3); 13C NMR (100MHz, DMSO) δ: 172.9,157.4,130.3,126.7,114.1,67.3,31.2,28.7,28.4,25.5,22.0,13.9.
Synthesizing of 6-oxygen in positive heptan base-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-bromo-2-Tetralone an intermediate of Sertraline, get 4-oxygen in positive heptan base-toluylic acid 20g (80.0mmol), 1,2-ethylene dichloride 240mL, thionyl chloride 21mL (296mmol), aluminum trichloride (anhydrous) 28g (209mmol), methylene dichloride 400mL, get white solid 6-oxygen in positive heptan base-2-Tetralone an intermediate of Sertraline 10g, productive rate 48%;
mp?72-74℃； 1H?NMR(400MHz，CDCl 3)δ：7.02(d，1H，J＝12.0Hz，-ArH)，6.77(t，1H，J＝4.0Hz，-ArH)，6.74(d，1H，J＝4.0Hz，-ArH)，3.95(t，2H，J＝7.0Hz，-CH 2-O)，3.51(s，2H，-CH 2-)，3.02(t，2H，J＝6.8Hz，-CH 2-)，2.53(t，2H，J＝6.8Hz，-CH 2-)，1.76-1.79(m，2H，-CH 2-)，1.43-1.47(m，2H，-CH 2-)，1.30-1.37(m，6H，3×-CH 2-)，0.89(3H，J＝6.8Hz，-CH 3)； 13C?NMR(100MHz，CDCl 3)δ：210.5，157.9，137.6，128.8，124.8，113.7，112.7，67.8，44.0，37.9，31.6，29.1，28.9，28.4，25.8，22.4，13.9。
3 ', 4 '-dihydro-6 '-positive oxygen base-spiral shell in heptan [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 6-oxygen in positive heptan base-2-Tetralone an intermediate of Sertraline 5.5g (21.1mmol), potassium cyanide 1.65g (25.4mmol), volatile salt 18.5g (192.7mmol), 50% ethanol 140mL, get white solid 3 ', 4 '-dihydro-6 '-positive oxygen base-spiral shell in heptan [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 3.2g, productive rate 46%;
mp?311-315℃； 1H?NMR(400MHz，DMSO)δ：10.66(s，1H，-NH-)，8.26(s，1H，-NH-)，7.15(d，1H，J＝8.0Hz，-ArH)，6.68-6.71(m，3H，3×-ArH)，3.89(t，2H，J＝7.0Hz，-CH 2-O)，3.02(d，1H，J＝16.8Hz，-CH-)，2.85-2.89(s，2H，-CH 2-)，2.68(d，1H，J＝16.8Hz，-CH-)，1.87-1.95(m，1H，-CH-)，1.76-1.79(m，1H，-CH-)，1.64-1.71(m，2H，-CH 2-)，1.27-1.39(m，8H，4×-CH 2-)，0.87(t，3H，J＝6.8Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：178.2，156.9，156.3，135.9，129.8，124.3，113.7，112.8，67.3，60.8，36.2，31.2，29.9，28.7，28.4，25.5，24.9，22.0，13.9。
Synthesizing of 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid
Get 3 ', 4 '-dihydro-6 '-positive oxygen base-spiral shell in heptan [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7g (21.2mmol), sodium hydroxide 20g (500mmol), water 200m L, get white solid 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
mp?323-326℃； 1H?NMR(400MHz，DMSO)δ：6.95(d，1H，J＝8.0Hz，-ArH)，6.64-6.68(m，2H，2×-ArH)，6.19(s，1H，-NH-)，5.46(s，2H，-NH 2)，3.89(t，2H，J＝6.4Hz，-CH 2-O)，3.02(d，1H，J＝16.4Hz，-CH-)，2.86(d，1H，J＝16.4Hz，-CH-)，2.66-2.73(m，2H，-CH 2-)，2.24-2.28(m，1H，-CH-)，1.82-1.88(m，1H，-CH-)，1.63-1.69(m，2H，-CH 2-)，1.27-1.38(m，8H，4×-CH 2-)，0.85-0.88(m?3H，-CH 3)； 13C?NMR(100MHz，DMSO)δ：176.0，158.5，156.7，136.1，130.0，125.4，113.5，112.6，67.3，56.3，36.4，31.2，28.7，28.4，25.5，25.2，22.0，13.9。
Synthesizing of 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Get 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (5.7mmol), lithium aluminum hydride 0.7g (18.4mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction is spin-dried for solvent and gets crude product 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 27% of getting; Mp 222-224 ℃; 1H NMR (400MHz, DMSO) δ: 8.21 (s, 3H ,-NH 3 +), 6.97 (d, 1H, J=8.4Hz ,-ArH), 6.69 (d, 1H, J=8.4Hz ,-ArH), 6.67 (s, 1H ,-ArH), 5.53 (t, 1H, J=4.8Hz ,-OH), 3.89 (t, 2H, J=6.4Hz ,-CH 2-O), 3.42 (t, 2H, J=4.8Hz ,-CH 2-), 2.87 (s, 2H ,-CH 2-) 2.69-2.78 (m, 2H ,-CH 2-), 1.86-1.98 (m, 2H ,-CH 2-), 1.63-1.72 (m, 2H ,-CH 2-), 1.27-1.39 (m, 8H, 4 *-CH 2-), 0.86 (t, 3H, J=6.8Hz ,-CH 3); 13C NMR (100MHz, DMSO) δ: 156.9,135.6,129.9,124.2,113.6,112.9,67.3,62.6,55.9,33.3,31.2,28.7,28.4,27.2,25.4,25.0,21.9,13.9; Mass spectrum ESI-MS:(C 18H 29NO 2.HCl) (M ++ 1) 291; Infrared spectra IR (KBr) vcm -1: 3439,2926,2856,1610,1502,1466,1400,1273,1157,1053,796.
Embodiment 6:
The synthetic method of 2-amino-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-011) and hydrochloride (FC-012) (hereinafter to be referred as FC-011, FC-012) thereof is as follows:
Figure G2008100516876D0000261
Synthesizing of 2-(1, the 3-dioxolane)-6-bromo-1,2,3,4-tetrahydrochysene-naphthalene
Get 6-bromo-2-Tetralone an intermediate of Sertraline (FC-021A) 10g (44.4mmol), ethylene glycol 4g (66.7mmol), tosic acid 0.5g (2.6mmol), hexanaphthene 100mL, heating reflux reaction 4h in the three-necked bottle of water trap is housed, cooling, add saturated sodium bicarbonate and be washed till neutrality, ethyl acetate extraction, anhydrous magnesium sulfate drying is spin-dried for solvent silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 10), get faint yellow solid 2-(1, the 3-dioxolane)-and 6-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g, productive rate 83%; 1H NMR (400MHz, CDCl 3) δ: 7.25 (s, 1H ,-ArH), 7.23 (d, 1H, J=8.0Hz ,-ArH), 6.92 (d, 1H, J=8.0Hz ,-ArH), 4.00-4.05 (m, 4H, 2 *-CH 2-), 2.95 (t, 2H, J=8.0Hz ,-CH 2-), 2.91 (s, 2H ,-CH 2-), 1.92 (t, 2H, J=8.0Hz ,-CH 2-); 13C NMR (100MHz, CDCl 3) δ: 137.4,133.3,130.8,130.5,128.5,119.2,107.4,64.2,38.4,31.1,27.5.
Synthesizing of 2-(1, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene
Get phenol 4.2g (44.8mmol), 2-(1, the 3-dioxolane)-6-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.3mmol), salt of wormwood 12.4g (106.6mmol), Red copper oxide 7.2g (44.8mmol), pyridine 200mL, heating reflux reaction 24h under nitrogen protection, cooling, the 500mL that adds methylene chloride filters, filtrate is spin-dried for silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 5), get faint yellow oily 2-(1, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene 8.5g, productive rate 81%; 1H NMR (400MHz, CDCl 3) δ: 7.31-7.33 (m, 2H, 2 *-ArH), 7.05-7.09 (m, 1H ,-ArH), 6.97-7.02 (m, 3H, 3 *-ArH), 6.78-6.81 (m, 2H, 2 *-ArH), 4.00-4.07 (m, 4H, 2 *-CH 2-), 2.92-2.99 (m, 4H, 2 *-CH 2-), 1.93-1.98 (m, 2H ,-CH 2-); 13C NMR (100MHz, CDCl 3) δ: 157.6,155.1,136.8,130.3,129.6,129.4,122.8,118.7,118.5,117.0,108.2,64.5,38.5,31.5,28.1.
Synthesizing of 6-phenoxy group-2-Tetralone an intermediate of Sertraline
Get 2-(1, the 3-dioxolane)-and 6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene 9g (31.9mmol), right-toluenesulphonic acids 3.7g (21.3mmol), acetone 300mL, stirring at room reaction 1h, acetone is spin-dried for, and adds saturated sodium carbonate solution 100mL, dichloromethane extraction, the organic layer anhydrous magnesium sulfate drying, solvent evaporated silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 10), get white solid 6-phenoxy group-2-Tetralone an intermediate of Sertraline 7g, productive rate 86%; Mp 28-30 ℃; 1H NMR (400MHz, CDCl 3) δ: 7.32-7.36 (m, 2H, 2 *-ArH), 7.07-7.13 (m, 2H, 2 *-ArH), 6.99-7.02 (m, 2H, 2 *-ArH), 6.86-6.89 (m, 2H, 2 *-ArH), 3.56 (s, 2H ,-CH 2-), 3.01 (t, 2H, J=8.0Hz ,-CH 2-), 2.54 (t, 2H, J=8.0Hz ,-CH 2-); 13C NMR (100MHz, CDCl 3) δ: 210.2,157.1,155.9,138.2,129.6,129.3,127.9,123.2,118.7,117.9,117.3,44.3,37.8,28.3.
3 ', 4 '-dihydro-6 '-phenoxy group-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 6-phenoxy group-2-Tetralone an intermediate of Sertraline 7g (29.4mmol), potassium cyanide 2.3g (35.3mmol), volatile salt 25.5g (264.6mmol), 50% ethanol 180mL, get solid 3 ', 4 '-dihydro-6 '-phenoxy group-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7.0g, productive rate 77%;
mp?313-315℃； 1H?NMR(400MHz，DMSO)δ：10.69(s，1H，-NH-)，8.28(s，1H，-NH-)，7.36-7.40(m，2H，2×-ArH)，7.09-7.14(m，2H，2×-ArH)，6.98(d，2H，J＝7.6Hz，2×-ArH)，6.78-6.81(m，2H，2×-ArH)，3.08(d，1H，J＝16.0Hz，-CH-)，2.86-2.91(m，2H，-CH 2-)，2.76(d，1H，J＝16.0Hz，-CH-)，1.82-1.94(m，1H，-CH-)，1.78-1.82(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，157.1，156.3，154.3，134.5，130.6，130.2，129.9，123.0，119.1，118.0，116.9，60.5，36.9，30.1，24.1。
Synthesizing of 2-urea groups-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-phenoxy group-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7g (22.7mmol), sodium hydroxide 20g (500mmol), water 200mL, get white solid 2-urea groups-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
Mp＞300 ℃ decomposition; 1H NMR (400MHz, DMSO) δ: 12.2 (brs, 1H ,-COOH), 7.36 (t, 2H, J=8.0Hz, 2 *-ArH), 7.07-7.13 (m, 2H, 2 *-ArH), 6.98 (d, 2H, J=8.4Hz, 2 *-ArH), 6.75-6.78 (m, 2H, 2 *-ArH), 6.16 (s, 1H ,-NH-), 5.36 (s, 1H ,-NH-), 3.17 (d, 1H, J=16.4Hz ,-CH-), 2.98 (d, 1H, J=16.4Hz ,-CH-), 2.71-2.77 (m, 2H ,-CH 2-), 2.27-2.30 (m, 1H ,-CH-), 1.91-1.95 (m, 1H ,-CH-); 13C NMR (100MHz, DMSO) δ: 175.9,158.5,157.0,154.4,136.9,130.7,129.9,129.1,123.1,118.3,118.2,116.6,56.2,36.5,28.8,25.1.
Synthesizing of 2-amino-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (6.1mmol), lithium aluminum hydride 0.7g (18.4mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h adds 1N NaOH 100mL, ethyl acetate extraction under the ice bath, be spin-dried for solvent and get crude product 2-urea groups-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-6-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 24% of getting;
Mp 215-217 ℃; 1H NMR (400MHz, DMSO) δ: 8.13 (brs, 3H ,-NH 3 +), 7.37 (t, 2H, J=8.0Hz, 2 *-ArH), 7.12 (d, 2H, J=8.0Hz, 2 *-ArH), 6.97 (d, 2H, J=8.0Hz, 2 *-ArH), 6.79 (m, 2H, 2 *-ArH), 5.55 (t, 1H, J=5.2Hz ,-OH), 3.45 (d, 2H, J=5.2Hz ,-CH 2-), 2.93 (s, 2H ,-CH 2-), 2.73-2.90 (m, 2H ,-CH 2-), 1.91-1.93 (m, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 156.9,154.7,136.5,130.6,129.9,127.7,123.2,118.4,118.3,116.9,62.7,55.9,33.4,27.0,24.8; Mass spectrum ESI-MS:(C 17H 19NO 2.HCl) (M ++ 1) 269; Infrared spectra IR (KBr) vcm -1: 3394,3026,2933,2638,2552,2037,1613,1592,1489,1259,1236,1164,1062,945,873,757,692.
Embodiment 7:
The synthetic method of 2-amino-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-013) and hydrochloride (FC-014) (hereinafter to be referred as FC-013, FC-014) thereof is as follows:
Figure G2008100516876D0000291
Synthesizing of 2-(1, the 3-dioxolane)-6-(3-chlorophenoxy)-1,2,3,4 tetrahydrochysenes-naphthalene
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, between getting-chlorophenol 10g (77.2mmol), (FC-015A) 10g (37.2mmol), salt of wormwood 20g (148.8mmol), Red copper oxide 12.3g (77.2mmol), pyridine 200mL, get faint yellow oily 2-(1, the 3-dioxolane)-6-(3-chlorophenoxy)-1,2,3,4 tetrahydrochysenes-naphthalene 8.5g, productive rate 73%;
1H?NMR?(400MHz，CDCl 3)δ：7.22(t，1H，J＝8.0Hz，-ArH)，7.02-7.05(m，2H，2×-ArH)，6.95(t，1H，J＝2.4Hz，-ArH)，6.86(dd，1H，J＝8.0Hz，J＝2.0Hz，-ArH)，6.79-6.82(m，2H，2×-ArH)，4.03-4.06(m，4H，2×-CH 2-)，2.94-2.98(m，4H，2×-CH 2-)，1.95(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：158.6，154.1，137.1，134.8，130.5，130.3，130.2，122.7，119.2，118.2，117.4，116.2，108.1，64.5，38.5，31.4，28.0。
Synthesizing of 6-(3-chlorophenoxy)-2-Tetralone an intermediate of Sertraline
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-6-(3-chlorophenoxy)-1,2,3,4 tetrahydrochysenes-naphthalene 9g (28.5mmol), right-toluenesulphonic acids 3.3g (18.9mmol), acetone 300mL, get white solid compound 6-(3-chlorophenoxy)-2-Tetralone an intermediate of Sertraline 7g, productive rate 89%;
mp?67-69℃； 1H?NMR(400MHz，CDCl 3)δ：7.25(t，1H，J＝8.0Hz，-ArH)，7.11(d，1H，J＝8.0Hz，-ArH)，7.07(dd，1H，J＝8.0Hz，J＝0.8Hz，-ArH)，6.98(t，1H，J＝2.0Hz，-ArH)，6.87-6.91(m，3H，3×-ArH)，3.58(s，2H，-CH 2-)，3.04(t，2H，J＝8.0Hz，-CH 2-)，2.56(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：158.2，154.9，138.5，134.9，130.4，129.5，128.8，123.1，118.5，117.8，116.5，44.3，37.7，28.3。
3 ', 4 '-dihydro-6 '-(3 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 6-(3-chlorophenoxy)-2-Tetralone an intermediate of Sertraline 7g (25.7mmol), potassium cyanide 2g (30.9mmol), volatile salt 22.2g (231.3mmol), 50% ethanol 180mL, solid 3 ', 4 '-dihydro-6 '-(3 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2; 5-diketone 7g, productive rate 80%;
mp?313-317℃； 1H?NMR(400MHz，DMSO)δ：10.7(s，1H，-NH-)，8.30(s，1H，-NH-)，7.39(t，1H，J＝8.0Hz，-ArH)，7.16(t，2H，J＝8.4Hz，2×-ArH)，7.00(t，1H，J＝2.0Hz，-ArH)，6.93-6.94(m，1H，-ArH)，6.85-6.88(m，2H，2×-ArH)，3.09(d，1H，J＝16Hz，-CH-)，2.88-2.91(m，2H，-CH 2-)，2.78(d，1H，J＝16Hz，-CH-)，1.92-1.94(m，1H，-CH-)，1.81-1.82(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，158.4，156.3，153.5，137.1，133.9，131.3，130.7，128.8，122.8，119.2，117.6，117.4，116.5，60.7，36.3，29.7，24.8。
Synthesizing of 2-urea groups-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-(3 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4; 2 ' (1 ' H)-naphthalene]-2; 5-diketone 7g (20.5mmol), sodium hydroxide 20g (500mmol), water 200mL; get white solid 2-urea groups-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
mp?311-315℃； 1H?NMR(400MHz，DMSO)δ：7.36(t，1H，J＝8.0Hz，-ArH)，7.12(d，1H，J＝8.0Hz，-ArH)，7.03(d，1H，J＝8.0Hz，-ArH)，6.98(s，1H，-ArH)，6.91(d，1H，J＝8.0Hz，-ArH)，6.74-6.77(m，2H，2×-ArH)，6.06(s，1H，-NH-)，5.61(s，2H，-NH 2)，3.18(d，1H，J＝16.8Hz，-CH-)，3.00(d，1H，J＝16.8Hz，-CH-)，2.77-2.81(m，1H，-CH-)，2.64-2.68(m，1H，-CH-)，2.27-2.32(m，1H，-CH-)，1.75-1.78(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.8，158.3，153.4，137.1，133.8，131.3，130.8，129.9，122.8，118.8，117.7，117.0，116.5，56.1，36.6，28.6，24.9。
Synthesizing of 2-amino-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (5.6mmol), lithium aluminum hydride 0.6g (16.6mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction, be spin-dried for solvent and get crude product 2-urea groups-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-6-(3-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.5g, the productive rate 26% of getting;
Mp 212-214 ℃; 1H NMR (400MHz, DMSO) δ: 8.15 (brs, 3H ,-NH 3 +), 7.38 (t, 1H, J=8.0Hz ,-ArH), 7.09-7.18 (m, 2H, 2 *-ArH), 7.00 (t, 1H, J=2.0Hz ,-ArH), 6.92-6.98 (m, 1H ,-ArH), 6.86-6.88 (m, 2H, 2 *-ArH), 5.56 (s, 1H ,-OH), 3.45 (s, 2H ,-CH 2-), 2.89 (s, 2H ,-CH 2-), 2.67-2.80 (m, 2H ,-CH 2-), 1.92 (t, 2H, J=6.8Hz ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 158.2,153.7,136.8,133.8,131.4,130.8,128.5,122.9,119.1,117.8,117.4,116.5,62.8,55.8,33.5,27.0,24.8; Mass spectrum ESI-MS:(C 17H 18ClNO 2.HCl) (M ++ 1) 303; Infrared spectra IR (KBr) vcm -1: 3421,3315,3023,2931,2638,2550,2037,1588,1499,1471,1432,1302,1266,1240,1148,1088,1055,951,881,772,679.
Embodiment 8:
The synthetic method of 2-amino-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-015) and hydrochloride (FC-016) (hereinafter to be referred as FC-015, FC-016) thereof is as follows:
Figure G2008100516876D0000311
Synthesizing of 2-(1, the 3-dioxolane)-6-(4-chlorophenoxy)-1,2,3,4 tetrahydrochysenes-naphthalene
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get right-chlorophenol 10g (77.2mmol), 2-(1, the 3-dioxolane)-6-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.2mmol), salt of wormwood 20g (148.8mmol), Red copper oxide 12.3g (77.2mmol), pyridine 200mL gets faint yellow oily compound 2-(1, the 3-dioxolane)-and 6-(4-chlorophenoxy)-1,2,3,4 tetrahydrochysenes-naphthalene 8.5g, productive rate 73%;
1H?NMR(400MHz，CDCl 3)δ：7.23-7.27(m，2H，2×-ArH)，7.02(d，1H，J＝8.4Hz，-ArH)，6.89-6.92(m，2H，2×-ArH)，6.76-6.79(m，2H，2×-ArH)，4.02-4.06(m，4H，2×-CH 2-)，2.92-2.96(m，4H，2×-CH 2-)，1.94(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：156.3，154.7，137.0，130.5，129.8，129.5，128.8，119.6，118.7，117.0，108.1，38.5，31.4，28.1。
Synthesizing of 6-(4-chlorophenoxy)-2-Tetralone an intermediate of Sertraline
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-6-(4-chlorophenoxy)-1,2,3,4 tetrahydrochysenes-naphthalene 9g (28.5mmol), right-toluenesulphonic acids 3.3g (18.9mmol), acetone 300mL, get white solid compound 6-(4-chlorophenoxy)-2-Tetralone an intermediate of Sertraline 7g, productive rate 89%;
mp?83-85℃； 1H?NMR(400MHz，CDCl 3)δ：7.29(d，1H，J＝2.4Hz，-ArH)，7.28(d，1H，J＝2.4Hz，-ArH)，7.09(d，1H，J＝8.0Hz，-ArH)，6.93-6.95(m，2H，2×-ArH)，6.85-6.88(m，2H，2×-ArH)，3.56(s，2H，-CH 2-)，3.02(t，2H，J＝6.8Hz，-CH 2-)，2.55(t，2H，J＝6.8Hz，-CH 2-)； 13CNMR(100MHz，CDCl 3)δ：209.9，155.9，155.7，138.4，129.7，129.5，128.4，128.2，119.9，118.1，117.4，44.3，37.8，28.4。
3 ', 4 '-dihydro-6 '-(4 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get compound 6-(4-chlorophenoxy)-2-Tetralone an intermediate of Sertraline 7g (25.7mmol), potassium cyanide 2g (30.9mmol), volatile salt 22.2g (231.3mmol), 50% ethanol 180mL, solid chemical compound 3 ', 4 '-dihydro-6 '-(4 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2; 5-diketone 7.0g, productive rate 80%;
mp?308-310℃； 1H?NMR(400MHz，DMSO)δ：10.7(s，1H，-NH-)，8.29(s，1H，-NH-)，7.40-7.44(m，2H，2×-ArH)，7.13(d，1H，J＝8.0Hz，-ArH)，6.84-7.01(m，2H，2×-ArH)，6.82-6.84(m，2H，2×-ArH)，3.08(d，1H，J＝16.0Hz，-CH-)，2.86-2.88(m，2H，-CH 2-)，2.77(d，1H，J＝16.0Hz，-CH-)，1.82-1.95(m，1H，-CH-)，1.78-1.81(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，156.3，156.0，154.1，136.9，130.5，129.7，128.4，126.8，119.7，118.7，116.9，60.7，36.3，29.7，24.8。
Synthesizing of 2-urea groups-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-(4 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4; 2 ' (1 ' H)-naphthalene]-2; 5-diketone 7g (20.5mmol), sodium hydroxide 20g (500mmol), water 200mL; get white solid compound 2-urea groups-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 80%;
mp?303-307℃； 1H?NMR(400MHz，DMSO)δ：12.2(brs，1H，-COOH)，7.40(d，2H，J＝8.8Hz，2×-ArH)，7.08(d，1H，J＝8.0Hz，-ArH)，6.98(d，2H，J＝8.8Hz，2×-ArH)，6.75-6.79(m，2H，2×-ArH)，6.25(s，1H，-NH-)，5.51(s，-2H，-NH 2)，3.08(d，1H，J＝16.8Hz，-CH-)，3.01(d，1H，J＝16.8Hz，-CH-)，2.70-2.72(m，2H，-CH 2-)，2.25-2.28(m，1H，-CH-)，1.82-1.86(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：176.0，158.4，156.1，153.7，137.3，130.6，130.2，129.7，126.6，119.7，118.4，116.7，56.4，36.5，28.9，25.3。
Synthesizing of 2-amino-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (5.6mmol), lithium aluminum hydride 0.6g (16.6mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction, be spin-dried for solvent and get crude product 2-urea groups-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-6-(4-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.5g, the productive rate 26% of getting;
Mp 206-208 ℃; 1H NMR (400MHz, DMSO) δ: 8.15 (brs, 3H ,-NH 3 +), 7.37 (t, 1H, J=8.0Hz ,-ArH), 7.12 (d, 2H, J=8.0Hz, 2 *-ArH), 6.78-6.81 (m, 2H, 2 *-ArH), 5.56 (t, 1H, J=5.2Hz ,-OH), 3.45 (d, 2H, J=5.2Hz ,-CH 2-), 2.88 (s, 2H ,-CH 2-), 2.75-2.79 (m, 2H ,-CH 2-), 1.91-1.93 (m, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 155.9,154.3,136.7,130.8,129.9,129.8,128.1,126.8,119.8,118.6,118.3,117.1,62.8,55.8,33.4,27.0,24.8; Mass spectrum ESI-MS:(C 17H 18ClNO 2.HCl) (M ++ 1) 303; Infrared spectra IR (KBr) vcm -1: 3312,3021,2921,2638,2550,2037,1613,1590,1517,1502,1486,1443,1266,1245,1162,1089,1055,1011,949,867,833,806.
Embodiment 9:
The synthetic method of 2-amino-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthyl ethyl alcohol (FC-017) and hydrochloride (FC-018) (hereinafter to be referred as FC-017, FC-018) thereof is as follows:
Figure G2008100516876D0000341
Synthesizing of 2-(1, the 3-dioxolane)-6-(2-chlorophenoxy)-1,2,3,4 naphthanes
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get neighbour-chlorophenol 10g (77.2mmol), (FC-015A) 10g (37.2mmol), salt of wormwood 20g (148.8mmol), Red copper oxide 12.3g (77.2mmol), pyridine 200mL, get faint yellow oily compound 2-(1, the 3-dioxolane)-6-(2-chlorophenoxy)-1,2,3,4 naphthane 8.5g, productive rate 73%;
1H?NMR(400MHz，CDCl 3)δ：7.44(dd，1H，J＝1.6Hz，J＝8.0Hz，-ArH)，7.17-7.21(m，1H，-ArH)，7.06(t，1H，J＝8.0Hz，-ArH)，7.00(d，1H，J＝8.4Hz，-ArH)，6.95(d，1H，J＝8.0Hz，-ArH)，6.74-6.76(m，2H，2×-ArH)，4.02-4.05(m，4H，2×-CH 2-)，2.92-2.96(m，4H，2×-CH 2-)，1.94(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：154.8，152.7，136.8，130.5，130.3，129.4，127.7，124.1，120.2，117.6，115.9，108.1，64.3，38.4，31.4，27.9。
Synthesizing of 6-(2-chlorophenoxy)-2-Tetralone an intermediate of Sertraline
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-6-(2-chlorophenoxy)-1,2,3,4 naphthane 9g (28.5mmol), right-toluenesulphonic acids 3.3g (18.9mmol), acetone 300mL, get white solid compound 6-(2-chlorophenoxy)-2-Tetralone an intermediate of Sertraline 7g, productive rate 89%;
mp?20-22℃； 1H?NMR(400MHz，CDCl 3)δ：7.46(dd，1H，J＝1.6Hz，J＝8.0Hz，-ArH)，7.21-7.26(m，1H，-ArH)，7.11(dd，1H，J＝1.6Hz，J＝8.0Hz，-ArH)，7.07(d，1H，J＝7.6Hz，-ArH)，7.00(dd，1H，J＝1.6Hz，J＝8.0Hz，-ArH)，6.83-6.84(m，1H，-ArH)，6.79-6.82(dd，1H，J＝1.6Hz，J＝8.0Hz，-ArH)，3.55(s，2H，-CH 2-)，3.02(t，2H，J＝8.0Hz，-CH 2-)，2.54(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：155.6，152.1，138.2，130.6，129.2，127.9，127.8，125.6，124.6，120.7，116.8，116.0，44.1，37.6，28.2。
3 ', 4 '-dihydro-6 '-(2 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 6-(2-chlorophenoxy)-2-Tetralone an intermediate of Sertraline 7g (25.7mmol), potassium cyanide 2g (30.9mmol), volatile salt 22.2g (231.3mmol), 50% ethanol 180mL, solid chemical compound 3 ', 4 '-dihydro-6 '-(2 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2; 5-diketone 7.0g, productive rate 79.5%;
mp?299-301℃； 1H?NMR(400MHz，DMSO)δ：10.2(brs，1H，-NH-)，8.08(s，1H，-NH-)，7.56(d，1H，J＝8.0Hz，-ArH)，7.35(t，1H，J＝8.0Hz，-ArH)，7.19(t，1H，J＝8.0Hz，-ArH)，7.04-7.11(m，2H，2×-ArH)，6.73(s，2H，2×-ArH)，3.07(d，1H，J＝16.8Hz，-CH-)，2.87-2.89(m，2H，-CH 2-)，2.76(d，1H，J＝16.8Hz，-CH-)，1.93-1.98(m，1H，-CH-)，1.79-1.82(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，156.3，153.6，137.1，131.3，130.7，128.8，122.8，119.2，117.6，117.4，116.5，60.7，36.3，29.7，24.8。
Synthesizing of 2-urea groups-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-(2 "-chlorophenoxy)-spiral shell [tetrahydroglyoxaline-4; 2 ' (1 ' H)-naphthalene]-2; 5-diketone 7g (20.5mmol), sodium hydroxide 20g (500mmol), water 200mL; get white solid compound 2-urea groups-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
mp?298-300℃； 1H?NMR(400MHz，DMSO)δ：12.2(brs，1H，-COOH)，7.57(d，1H，J＝8.0Hz，-ArH)，7.35(t，1H，J＝7.6Hz，-ArH)，7.19(t，1H，J＝7.6Hz，-ArH)，7.03-7.08(m，2H，2×-ArH)，6.67-6.71(m，2H，2×-ArH)，6.27(s，1H，-NH-)，5.49(s，2H，-NH 2)，3.08(d，1H，J＝16.8Hz，-CH-)，2.98(d，1H，J＝16.8Hz，-CH-)，2.68-2.76(m，2H，-CH 2-)，2.25-2.28(m，1H，-CH-)，1.81-1.88(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.9，158.4，154.2，151.8，137.1，130.6，129.5，128.7，125.1，124.4，120.7，116.9，115.2，56.4，36.5，28.8，25.3。
Synthesizing of 2-amino-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthyl ethyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (5.6mmol), lithium aluminum hydride 0.6g (16.6mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction, be spin-dried for solvent and get crude product 2-urea groups-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-6-(2-chlorophenoxy)-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.5g, the productive rate 26% of getting;
Mp 196-197 ℃; 1H NMR (400MHz, DMSO) δ: 8.14 (brs, 3H ,-NH 3 +), 7.57 (dd, 1H, J=8.0Hz, J=1.6Hz,-ArH), 7.33-7.39 (m, 1H ,-ArH), 7.18-7.23 (m, 1H ,-ArH), 7.12 (d, 1H, J=8.4Hz,-ArH), 7.05 (dd, 1H, J=8.0Hz, J=1.6Hz,-ArH), 6.73-6.79 (m, 2H, 2 *-ArH), 5.55 (s, 1H ,-OH), 3.44 (s, 2H ,-CH 2-), 2.88 (s, 2H ,-CH 2-), 2.67-2.80 (m, 2H ,-CH 2-), 1.90 (s, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 154.6,151.7,136.6,130.6,129.9,128.7,127.7,125.2,124.4,120.8,117.1,115.6,62.8,55.8,33.4,27.0,24.8; Mass spectrum ESI-MS:(C 17H 18ClNO 2.HCl) (M ++ 1) 303; Infrared spectra IR (KBr) vcm -1: 3410,3316,3007,2932,2636,2553,2022,1612,1582,1500,1477,1444,1269,1245,1149,1058,950,864,753,681.
Embodiment 10:
2-amino-6-(3-methoxyl group phenoxy group)-1,2,3, the synthetic method of 4-tetrahydrochysene-2-naphthyl ethyl alcohol (FC-019) and hydrochloride (FC-020) (hereinafter to be referred as FC-019, FC-020) thereof is as follows:
Figure G2008100516876D0000361
Synthesizing of 2-(1, the 3-dioxolane)-6-(3-methoxyl group phenoxy group)-1,2,3,4 tetrahydrochysenes-naphthalene
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, between getting-and methoxyphenol 9.3g (74.6mmol), 2-(1, the 3-dioxolane)-6-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.3mmol), salt of wormwood 20g (149.2mmol), Red copper oxide 11.9g (74.6mmol), pyridine 200mL gets faint yellow oily compound 2-(1, the 3-dioxolane)-and 6-(3-methoxyl group phenoxy group)-1,2,3,4 tetrahydrochysenes-naphthalene 8.5g, productive rate 73%;
1H?NMR(400MHz，CDCl 3)δ：7.19(t，1H，J＝8.1Hz，-ArH)，7.01(d，1H，J＝8.0Hz，-ArH)，6.79-6.82(m，2H，2×-ArH)，6.62(dd，1H，J＝8.0Hz，J＝1.2Hz，-ArH)，6.54-6.56(m，2H，2×-ArH)，4.03-4.05(m，4H，2×-CH 2-)，3.77(s，3H，-OCH 3)，2.93-2.96(m，4H，2×-CH 2-)，1.94(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：160.8，158.8，154.8，136.8，130.3，129.9，129.5，118.7，117.1，110.5，108.4，108.2，104.4，64.4，55.2，38.5，31.5，28.0。
Synthesizing of 6-(3-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-6-(3-methoxyl group phenoxy group)-1,2,3,4 tetrahydrochysenes-naphthalene 9g (28.8mmol), right-toluenesulphonic acids 3.3g (19.2mmol), acetone 300mL, get white solid compound 6-(3-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline 7g, productive rate 90%;
mp?93-95℃； 1H?NMR(400MHz，CDCl 3)δ：7.23(t，1H，J＝8.0Hz，-ArH)，7.08(d，1H，J＝8.0Hz，-ArH)，6.87-6.91(m，2H，2×-ArH)，6.66(dd，1H，J＝2.0Hz，J＝8.4Hz，-ArH)，6.57-6.59(m，2H，2×-ArH)，3.78(s，3H，-OCH 3)，3.56(s，2H，-CH 2-)，3.02(t，2H，J＝8.0Hz，-CH 2-)，2.55(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：210.2，160.8，158.4，155.7，138.2，130.1，129.3，128.1，118.2，117.5，110.8，108.7，104.8，55.3，44.3，37.8，28.3。3 ', 4 '-dihydro-6 '-(3 "-methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 6-(3-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline 7g (26.2mmol), potassium cyanide 2g (31.3mmol), volatile salt 22.6g (235.8mmol), 50% ethanol 180mL, white solid compound 3 ', 4 '-dihydro-6 '-(3 "-methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2; 5-diketone 7g, productive rate 79%;
mp?306-310℃； 1H?NMR(400MHz，DMSO)δ：10.70(s，1H，-NH-)，8.30(s，1H，-NH-)，7.24-7.33(m，2H，2×-ArH)，7.07-7.10(m，1H，-ArH)，6.86(d，1H，J＝8.0Hz，-ArH)，6.81(d，1H，J＝8.0Hz，-ArH)，6.51-6.55(m，2H，2×-ArH)，3.73(s，3H，-OCH 3)，3.08(d，1H，J＝16.0Hz，-CH-)，2.87(s，2H，-CH 2-)，2.76(d，1H，J＝16.0Hz，-CH-)，1.92-1.94(m，1H，-CH-)，1.78-1.81(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，160.6，130.4，130.3，127.9，118.6，116.9，110.2，108.6，104.4，60.7，55.2，36.3，29.8，24.8。
Synthesizing of 2-urea groups-6-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-(3 "-the methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4; 2 ' (1 ' H)-naphthalene]-2; 5-diketone 7g (20.7mmol), sodium hydroxide 20g (500mmol), water 200mL; get white solid compound 2-urea groups-6-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
mp?303-305℃； 1H?NMR(400MHz，DMSO)δ：12.2(brs，1H，-COOH)，7.25(t，1H，J＝8.4Hz，-ArH.)，7.08(d，1H，J＝8.4Hz，-ArH.)，6.77(t，1H，J＝8.4Hz，-ArH.)，6.75(s，1H，-ArH)，6.68(dd，1H，J＝8.4Hz，J＝2.0Hz，-ArH)，6.54(t，1H，J＝2.0Hz，-ArH)，6.50(dd，1H，J＝8.0Hz，J＝2.0Hz，-ArH)，6.28(s，1H，-NH-)，5.48(s，2H，-NH 2)，3.73(s，3H，-OCH 3)，3.10(d，1H，J＝16.8Hz，-CH-)，2.95(d，1H，J＝16.8Hz，-CH-)，2.67-2.74(m，2H，-CH 2-)，2.24-2.27(m，1H，-CH-)，1.85-1.90(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.9，160.6，158.4，158.2，154.1，136.8，130.6，130.4，129.2，118.3，116.6，110.2，108.6，104.4，56.2，55.2，36.5，28.8，25.0。
2-amino-6-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthyl ethyl alcohol and hydrochloride thereof synthetic
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2g (5.6mmol), lithium aluminum hydride 0.6g (16.8mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction, be spin-dried for solvent and get crude product 2-urea groups-6-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether, be spin-dried for solvent and get crude product 2-amino-6-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the adularescent solid that adds diethyl ether is separated out, filter dry white solid 2-amino-6-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.5g, the productive rate 26% of getting;
Mp 198-200 ℃; 1H NMR (400MHz, DMSO) δ: 8.00 (brs, 3H ,-NH 3 +), 7.26 (t, 1H, J=8.0Hz ,-ArH.), 7.13 (d, 1H, J=8.0Hz ,-ArH.), 6.81-6.84 (m, 2H, 2 *-ArH), 6.70 (dd, 1H, J=8.0Hz, J=2.0Hz ,-ArH), 6.49-6.54 (m, 2H, 2 *-ArH), 5.56 (s, 1H ,-OH), 3.73 (s, 3H ,-OCH 3), 3.43 (d, 2H, J=4.0Hz ,-CH 2-), 2.67-2.92 (m, 4H, 2 *-CH 2-), 1.89 (s, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 106.6,158.1,154.5,136.5,130.6,130.4,127.7,118.5,116.9,110.2,108.7,104.4,62.8,55.8,55.2,33.4,27.1,24.8; Mass spectrum ESI-MS:(C 18H 21NO 3.HCl) (M ++ 1) 299; Infrared spectra IR (KBr) vcm -1: 3422,3315,3016,2909,2848,2638,2549,2037,1602,1590,1487,1449,1266,1138,1039,962,847,692.
Embodiment 11:
2-amino-6-[3-(benzyloxy) phenoxy group]-1,2,3, the synthetic method of 4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-021) and hydrochloride (FC-022) (hereinafter to be referred as FC-021, FC-022) thereof is as follows:
Figure G2008100516876D0000391
2-(1, the 3-dioxolane)-6-[3-(benzyloxy) phenoxy group]-1,2,3,4 tetrahydrochysenes-naphthalene synthetic
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get 3-benzyloxy phenol 11g (55.0mmol), 2-(1, the 3-dioxolane)-6-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.3mmol), salt of wormwood 15g (108.7mmol), Red copper oxide 8.0g (55.6mmol), pyridine 250mL gets faint yellow oily compound 2-(1, the 3-dioxolane)-6-[3-(benzyloxy) phenoxy group]-1,2,3,4 tetrahydrochysenes-naphthalene 10g, productive rate 70%;
1H?NMR(400MHz，CDCl 3)δ：7.34-7.41(m，5H，5×-ArH)，7.18(t，1H，J＝8.0Hz，-ArH)，6.01(d，1H，J＝8.0Hz，-ArH)，6.78-6.81(m，2H，2×-ArH)，6.67-6.69(m，1H，-ArH)，6.16(t，1H，J＝2.4Hz，-ArH)，6.56-6.58(m，1H，-ArH)，5.00(s，2H，-CH 2-O-)，4.00-4.04(m，4H，2×-CH 2-)，2.96-2.98(m，2H，-CH 2-)，2.93(t，2H，J＝6.8Hz，-CH 2-)，1.94(t，2H，J＝6.8Hz，-CH 2-)； 13CNMR(100MHz，CDCl 3)δ：159.9，158.8，154.7.136.8，136.7，130.3，129.9，129.6，128.5，127.9，127.4，118.9，117.2，110.8，109.2，108.2，105.3，69.9，64.4，38.5，31.5，28.0。
6-[3-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline synthetic
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-6-[3-(benzyloxy) phenoxy group]-1,2,3,4 tetrahydrochysenes-naphthalene 10g (25.8mmol), right-toluenesulphonic acids 3.0g (17.2mmol), acetone 200mL, get faint yellow solid compound 6-[3-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline 6.0g, productive rate 68%;
mp?118-120℃； 1H?NMR(400MHz，CDCl 3)δ：7.36-7.42(m，4H，4×-ArH)，7.32-7.34(m，1H，-ArH)，7.22(d，1H，J＝8.0Hz，-ArH)，7.07(d，1H，J＝8.0Hz，-ArH)，6.86-6.89(m，2H，2×-ArH)，6.72-6.74(m，1H，-ArH)，6.60-6.63(m，2H，2×ArH)，5.03(s，2H，-CH 2-O-)，3.56(s，2H，-CH 2-)，3.01(t，2H，J＝8.0Hz，-CH 2-)，2.55(t，2H，J＝8.0Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：209.6，159.8，158.3，155.4，138.1，136.5，138.1，136.5，129.9，129.2，128.3，128.1，127.7，127.2，118.1，117.4，110.8，109.3，105.4，69.8，44.1，37.6，28.1。
3 ', 4 '-dihydro-6 '-[3 "-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone FC-003A, get 6-[3-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline 5.5g (16.0mmol), potassium cyanide 1.3g (20.0mmol), volatile salt 13.8g (143.75mmol), 50% ethanol 110mL, white solid compound 3 ', 4 '-dihydro-6 '-[3 "-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2; 5-diketone 4.0g, productive rate 63%;
mp?360-362℃； 1H?NMR(400MHz，DMSO)δ：10.70(s，1H，-NH-)，8.29(s，1H，-NH-)，7.33-7.44(m，5H，5×ArH)，7.26(t，1H，J＝8.4Hz，-ArH)，7.10(d，1H，J＝8.4Hz，-ArH)，6.76-6.80(m，3H，3×-ArH)，6.06(t，1H，J＝2.4Hz，-ArH)，6.52-6.54(m，1H，-ArH)，5.08(s，2H，-CH 2-O-)，3.08(d，1H，J＝16.0Hz，-CH-)，2.86-2.87(m，2H，-CH 2-)，2.76(d，1H，J＝16.0Hz，-CH-)，1.92-1.94(m，1H，-CH-)，1.80-1.82(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.11，159.7，158.3，156.3，154.2，136.7，130.4，128.4，128.0，127.8，127.7，118.7，116.9，110.4，109.4，105.1，69.3，60.7，36.3，29.8，24.8。
2-urea groups-6-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2 naphthoic acid synthetic
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-[3 "-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4; 2 ' (1 ' H)-naphthalene]-2; 5-diketone 4.0g (10.0mmol), sodium hydroxide 10.0g (250mmol), water 100mL; white solid compound 2-urea groups-6-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2 naphthoic acid 4.0g, productive rate 93%;
mp?322-326℃； 1H?NMR(400MHz，DMSO)δ：12.15(brs，1H，-COOH)，7.32-7.43(m，5H，5×-ArH)，7.25(t，1H，J＝8.0Hz，-ArH)，7.08(d，1H，J＝8.4Hz，-ArH)，6.74-6.77(m，3H，3×-ArH)，6.60(t，1H，J＝2.0Hz，-ArH)，6.51(dd，1H，J＝8.0Hz，J＝1.6Hz，-ArH)，6.27(s，1H，-NH-)，5.47(s，2H，-NH 2)，5.07(s，2H，-CH 2-O-)，3.32(s，2H，-CH 2-)，2.93(q，2H，J＝16.8Hz，-CH 2-)，2.68-2.74(m，2H，-CH 2-)，1.92-1.94(m，1H，-CH-)，1.84-1.86(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.9，159.6，158.4，158.2，154.0，136.8，130.6，129.2，128.4，127.8，127.7，118.4，116.7，110.4，109.5，105.1，69.3，55.2，36.5，28.7，24.9。
2-amino-6-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof synthetic
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2 naphthoic acid 2.0g (4.6mmol), lithium aluminum hydride 0.35g (9.2mmol), tetrahydrofuran (THF) 50mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction, be spin-dried for solvent and get crude product 2-urea groups-6-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether, be spin-dried for solvent and get crude product 2-amino-6-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the adularescent solid that adds diethyl ether is separated out, filter dry white solid 2-amino-6-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, productive rate 25%;
Mp 232-234 ℃; 1H NMR (400MHz, DMSO) δ: 8.18 (brs, 3H ,-NH 3 +), 7.24-7.41 (m, 5H, 5 *-ArH), 7.25 (t, 1H, J=8.0Hz ,-ArH), 7.12 (d, 1H ,-ArH), 6.78-6.81 (m, 3H, 3 *-ArH), 6.06 (s, 1H ,-ArH), 6.52 (d, 1H, J=8.0Hz ,-ArH), 5.55 (s, 1H ,-OH), 5.08 (s, 2H ,-CH 2-O-), 3.45 (s, 2H ,-CH 2-), 2.89 (s, 2H ,-CH 2-), 2.76-2.78 (m, 2H ,-CH 2-), 1.93 (s, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 159.6,158.1,154.4,136.8,136.5,130.6,136.5,130.6,130.4,128.4,127.8,127.6,118.5,117.0,110.4,109.6,105.1,69.3,62.7,55.9,33.4,26.9,24.8; Mass spectrum (C 24H 25NO 3.HCl): ESI-MS (M ++ 1) 375; Infrared spectra IR (KBr) vcm -1: 3380,3170,3025,2929,2874,2663,1601,1587,1537,1493,1445,1381,1256,1229,1177,1155,1138,1061,1023,767,743,689,682.
Embodiment 12:
2-amino-6-phenyl-1,2,3, the synthetic method of 4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-023) and hydrochloride (FC-024) (hereinafter to be referred as FC-023, FC-024) thereof is as follows:
Figure G2008100516876D0000411
Synthesizing of 6-bromo-2-Tetralone an intermediate of Sertraline
Get right-bromo-acid 20g (94mmol), 1,2-ethylene dichloride 240mL, thionyl chloride 21mL (296mmol), heating reflux reaction 4h is spin-dried for, 100mL adds methylene chloride, above-mentioned solution of acid chloride is added in the mixing solutions of the 300mL methylene dichloride that contains aluminum trichloride (anhydrous) 28g (209mmol), is being lower than 0 ℃ of feeding ethylene reaction down, question response finishes back (approximately 4h), add water 200mL, dichloromethane extraction, organic phase are used 1N HCl successively, the saturated sodium carbonate solution washing, anhydrous magnesium sulfate drying, steaming desolventizes silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 5), get white solid compound 6-bromo-2-Tetralone an intermediate of Sertraline 15g, productive rate 75%;
Synthesizing of 6-phenyl-2-Tetralone an intermediate of Sertraline
Get phenylo boric acid 4.8g (39.3mmol), 6-bromo-2-Tetralone an intermediate of Sertraline 6g (26.8mmol), palladium 0.12g (0.5mmol), thricyclohexyl phosphorus 0.48g (1.7mmol), three water potassiumphosphate 19.2g (72.2mmol), toluene 120mL, water 25mL, heating reflux reaction 3h under nitrogen protection, cooling, filter, add water 100mL, ethyl acetate extraction, anhydrous magnesium sulfate drying, be spin-dried for solvent silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 8), get faint yellow solid compound 6-phenyl-2-Tetralone an intermediate of Sertraline 5.6g, productive rate 93%; Mp 86-88 ℃; 1H NMR (400MHz, CDCl 3) δ: 7.59-7.60 (m, 2H, 2 *-ArH), 7.37-7.46 (m, 4H, 4 *-ArH), 7.36 (d, 1H, J=7.2Hz ,-ArH), 7.20 (d, 1H, J=7.6Hz ,-ArH), 3.63 (s, 2H ,-CH 2-), 3.13 (t, 2H, J=6.8Hz ,-CH 2-), 2.59 (t, 2H, J=6.8Hz ,-CH 2-); 13C NMR (100MHz, CDCl 3) δ: 210.3,140.6,139.8,136.9,132.2,128.7,128.5,127.2,126.9,126.2,125.5,44.6,38.1,28.4.
3 ', 4 '-dihydro-6 '-phenyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 6-phenyl-2-Tetralone an intermediate of Sertraline 6.0g (27.0mmol), potassium cyanide 2.1g (32.3mmol), volatile salt 23.5g (244.9mmol), 50% ethanol 190mL, get white solid compound 3 ', 4 '-dihydro-6 '-phenyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 5.5g, productive rate 70%;
mp?318-320℃； 1H?NMR(400MHz，DMSO)δ：10.73(s，1H，-NH-)，8.34(s，1H，-NH-)，7.63(d，2H，J＝8.0Hz，2×-ArH)，7.42-7.47(m，4H，4×-ArH)，7.35(d，1H，J＝8.0Hz，-ArH)，7.18(d，1H，J＝8.0Hz，-ArH)，3.15(d，1H，J＝16.0Hz，-CH-)，2.84-3.00(m，2H，-CH 2-)，7.18(d，1H，J＝16.0Hz，-CH-)，1.87-2.03(m，1H，-CH-)，1.84-1.86(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.2，156.3，140.1，137.9，135.4，132.0，129.6，128.9，127.2，126.7，126.4，124.3，60.8，36.6，30.1，24.9。
Synthesizing of 2-urea groups-6-phenyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-phenyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 6g (20.5mmol), sodium hydroxide 10g (250mmol), water 200mL, get white solid compound 2-urea groups-6-phenyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 4.5g, productive rate 81%;
mp?366-368℃； 1H?NMR(400MHz，DMSO)δ：12.32(s，1H，-CO 2H)，7.61(d，2H，J＝8.0Hz，2×-ArH)，7.43(t，2H，J＝7.6Hz，2×-ArH)，7.37-7.39(m，2H，2×-ArH)，7.33(t，1H，J＝7.2Hz，-ArH)，7.16(d，1H，J＝8.4Hz，-ArH)，6.36(s，1H，-NH)，5.51(s，2H，-NH 2)，3.19(d，1H，J＝16.0Hz，-CH-)，3.02(d，1H，J＝16.0Hz，-CH-)，2.81-2.87(m，2H，-CH 2-)，2.29-2.32(m，1H，-CH-)，1.88-1.96(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.9，158.4，140.2，137.7，135.5，133.3，129.8，128.8，127.1，126.6，126.4，124.1，56.2，36.8，29.1，25.0。
2-amino-6-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof synthetic
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-phenyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2g (6.4mmol), lithium aluminum hydride 0.73g (19.2mmol), tetrahydrofuran (THF) 50mL, stirring at room reaction 36h adds 1N NaOH 100mL, ethyl acetate extraction under the ice bath, be spin-dried for solvent and get crude product 2-urea groups-6-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-6-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-6-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.6g, the productive rate 32% of getting;
mp?256-258℃； 1H?NMR(400MHz，DMSO)δ：8.20(brs，3H，-NH 3 +)，7.62(d，2H，J＝7.2Hz，2×-ArH)，7.43-7.46(m，4H，4×-ArH)，7.35(d，1H，J＝7.2Hz，-ArH)，7.20(d，1H，J＝8.8Hz，-ArH)，5.5(brs，1H，-OH)，3.48(s，2H，-CH 2-)，2.95(s，2H，-CH 2-)，2.89-2.92(m，2H，-CH 2-)，1.98-1.99(m，2H，-CH 2-)； 13C?NMR(100MHz，DMSO)δ：139.9，138.1，135.2，131.9，129.7，128.8，127.2，126.7，126.4，124.4，62.8，55.9，33.8，27.3，24.8。Mass spectrum ESI-MS:(C 17H 19NO.HCl) (M ++ 1) 253; Infrared spectra IR (KBr) vcm -1: 3025,2930,2875,2658,2047,1605,1536,1485,1440,1406,1062,764,691.
Embodiment 13:
The synthetic method of 2-amino-6-n-octyl-8-chloro-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-025) and hydrochloride (FC-026) (hereinafter to be referred as FC-025, FC-026) thereof is as follows:
Figure G2008100516876D0000441
Synthesizing of 6-n-octyl-8-chloro-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-normal-butyl-2-Tetralone an intermediate of Sertraline, get 6,8-two chloro-2-Tetralone an intermediate of Sertraline 5g (23.4mmol), octane ylboronic acid 5g (31.6mmol), three water potassiumphosphate 21g (78.9mmol), thricyclohexyl phosphorus 0.7g (2.5mmol), palladium 0.25g (1.1mmol), toluene 100mL, water 5mL, get faint yellow solid 6-n-octyl-8-chloro-2-Tetralone an intermediate of Sertraline 4.5g, productive rate 78%;
mp?72-74℃； 1H?NMR(400MHz，CDCl 3)δ：7.07(s，2H，2×-ArH)，3.51(s，2H，-CH 2-)，3.03(t，2H，J＝6.4Hz，-CH 2-)，2.49-2.57(m，4H，2×-CH 2-)，1.48-1.53(m，2H，-CH 2-)，1.27-1.30(m，10H，5×-CH 2-)，0.88(t，3H，J＝6.4Hz，-CH 3)； 13C?NMR(100MHz，CDCl 3)δ：209.0，142.1，138.2，131.6，129.4，127.0，125.0，40.7，37.5，32.5，31.6，30.0，29.3，29.1，28.9，28.4，22.3，13.8。
3 ', 4 '-dihydro-6 '-n-octyl-8 '-chloro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 6-n-octyl-8-chloro-2-Tetralone an intermediate of Sertraline 5g (17.1mmol), potassium cyanide 1.3g (20.5mmol), volatile salt 14.7g (153.9mmol), 50% ethanolic soln 125mL, get white solid 3 ', 4 '-dihydro-6 '-n-octyl-8 '-chloro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 5.0g, productive rate 80%;
mp?267-269℃； 1H?NMR(400MHz，DMSO)δ：10.3(brs，1H，-NH)，8.27(s，1H，-NH-)，7.04(s，2H，2×-ArH)，2.93(d，1H，J＝17.2Hz，-CH-)，2.89(s，2H，-CH 2-)，2.46-2.50(m，2H，-CH 2-)，1.85-1.93(m，1H，-CH-)，1.76-1.79(m，1H，-CH-)，1.44(s，2H，-CH 2-)，1.24-1.27(m，10H，5×-CH 2-)，0.83-0.85(m，3H，-CH 3)； 13C?NMR(100MHz，DMSO)δ：178.2，156.3，143.2，137.5，130.1，129.6，125.9，125.7，60.6，33.6，31.6，31.2，29.4，29.3，28.8，28.7，28.6，25.1，22.0，13.9。
Synthesizing of 2-urea groups-6-n-octyl-8-chloro-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-n-octyl-8 '-chloro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 5.0g (13.8mmol), sodium hydroxide 10g (250mmol), water 100mL, get white solid 2-urea groups-6-n-octyl-8-chloro-1,2,3,4-tetrahydrochysene-2-naphthoic acid 3.8g, productive rate 83%;
mp?296-298℃； 1H?NMR(400MHz，DMSO)δ：6.99-7.04(m，2H，2×-ArH)，3.16(d，1H，J＝16.8Hz，-CH-)，2.76-2.84(m，3H，-CH-，-CH 2-)，2.45-2.47(m，2H，-CH 2-)，2.06-2.13(m，1H，-CH-)，1.90-1.97(m，1H，-CH-)，1.46-1.48(m，2H，-CH 2-)，1.25-1.29(m，10H，5×-CH 2-)，0.84-0.87(m，3H，-CH 3)； 13C?NMR(100MHz，DMSO)δ：172.5，142.1，137.1，129.6，125.3，124.9，124.8，57.2，32.1，31.2，30.5，28.8，28.5，28.2，28.0，27.8，25.0，21.1，12.8。
Synthesizing of 2-amino-6-n-octyl-8-chloro-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-n-octyl-8-chloro-1,2,3,4-tetrahydrochysene-2-naphthoic acid 1.0g (3.0mmol), lithium aluminum hydride 0.34g (8.9mmol), tetrahydrofuran (THF) 20mL, stirring at room reaction 12h adds water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-6-n-octyl-8-chloro-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the solid that added diethyl ether is separated out, and filters, dry white solid 2-amino-6-n-octyl-8-chloro-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 45% of getting;
Mp 193-195 ℃; 1H NMR (400MHz, DMSO) δ: 8.13 (s, 3H ,-NH 3 +), 7.03-7.07 (m, 1H ,-ArH), 6.93-6.98 (m, 1H ,-ArH), 3.42 (s, 2H ,-CH 2-), 2.90 (d, 1H, J=16.8Hz ,-CH-), 2.73-2.84 (m, 3H ,-CH-,-CH 2-), 2.46-2.48 (m, 2H ,-CH 2-), 1.87-1.91 (m, 2H ,-CH 2-), 1.46-1.48 (m, 2H ,-CH 2-), 1.23-1.28 (m, 10H, 5 *-CH 2-), 0.84 (t, 3H, J=6.8Hz ,-CH 3); 13C NMR (100MHz, DMSO) δ: 140.5,134.6,130.4,126.5,126.3,125.7,63.1,56.1,32.3,31.3,30.8,29.6,29.2,28.9,28.7,26.9,25.2,22.1,13.9; Mass spectrum ESI-MS:(C 19H 30ClNO.HCl) (M ++ 1) 323; Infrared spectra IR (KBr) vcm -1: 3387,3026,2924,2644,1992,2591,1493,1464,1109,1070,777,721.
Embodiment 14
2-amino-6-[3-(benzyloxy) thiophenyl]-1,2,3, the synthetic method of 4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-027) and hydrochloride (FC-028) (hereinafter to be referred as FC-027, FC-028) thereof is as follows:
Figure G2008100516876D0000461
Synthesizing of base thiophenol
1) m-sulfanilic acid 40g (0.17mol) is dissolved in the 500mL water, hydro-oxidation sodium 6.9g (0.17mol), it is standby to wait to clarify back adding Sodium Nitrite 12.4g (0.18mol).Get vitriol oil 48g, keep permanent bath the below 5 ℃, slowly drip above-mentioned solution, dropwise afterreaction 2h, add a small amount of urea again, cool off stand-by; This solution is dripped in 160g 10% vitriol oil (being warming up to 80 ℃), drip off in the 30min, reaction 1h, cooling, neutralization reaction liquid, the evaporate to dryness reaction solution, solid adds ethanol to be washed, and filters desalination, evaporate to dryness ethanol, get pale solid (hydroxy benzenesulfonic acid) 32g, this crude product directly carries out next step without purifying; Get a hydroxy benzenesulfonic acid (above-mentioned crude product) 30g, 250mL dehydrated alcohol, salt of wormwood 90g, reflux drips 44g bromotoluene and 50mL dehydrated alcohol mixing solutions, and 1.5h drips off, filtrate evaporate to dryness ethanol is filtered in cooling, add water and transfer pH=1, ethyl acetate extraction, anhydrous magnesium sulfate drying with hydrochloric acid, solvent evaporated adds methyl alcohol in refrigerator overnight, filters, get benzyloxy Phenylsulfonic acid 35g between the white powder solid, 72%
2) get a benzyloxy Phenylsulfonic acid 30g (0.11mol), DMF 200mL, dripping thionyl chloride 40g (0.33mol) under the ice bath, the reaction 0.5h after, room temperature reaction 2h, after the cooling with frozen water, ethyl acetate extraction, wash ester layer, anhydrous magnesium sulfate drying, solvent evaporated with saturated sodium bicarbonate solution, get benzyloxy benzene sulfonyl chloride 29g between the orange solid, 74%3) get a benzyloxy benzene sulfonyl chloride 20g (70.9mmol), acetic acid 200mL, stirring at room dissolving, add zinc powder 92.2g (1.4mol) in batches, backflow 1h, cooling adds water, ethyl acetate extraction, anhydrous magnesium sulfate drying, filter, concentrate benzyloxy thiophenol 15g between solid, 85.9%
2-(1, the 3-dioxolane)-6-[3-(benzyloxy) thiophenyl]-1,2,3,4 tetrahydrochysenes-naphthalene synthetic
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get a benzyloxy thiophenol 10g (46.3mmol), (FC-015A) 14.2g (52.8mmol), salt of wormwood 23g (166.7mmol), Red copper oxide 16g (111.9mmol), DMF 150mL, oily matter 2-(1, the 3-dioxolane)-6-[3-(benzyloxy) thiophenyl]-1,2,3,4 tetrahydrochysenes-naphthalene 14g, productive rate 75%;
1H?NMR(400MHz，CDCl 3)δ：7.36-7.39(m，3H，3×-ArH)，7.29-7.34(m，2H，2×-ArH)，7.26(s，1H，-ArH)，7.18-7.19(m，1H，-ArH)，7.17(s，1H，-ArH)，7.14(s，1H，-ArH)，7.00(t，1H，J＝8.0Hz，-ArH)，6.88-6.89(m，1H，-ArH)，6.85(d，1H，J＝8.0Hz，-ArH)，6.78(dd，1H，J＝8.0Hz，J＝1.6Hz)，5.00(s，2H，-OCH 2-)，4.03-4.05(m，4H，2×-CH 2-)，2.98(s，2H，-CH 2-)，2.94(t，2H，J＝6.8Hz，-CH 2-)，1.94(t，2H，J＝6.8Hz，-CH 2-)，1.57(s，2H，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：159.1，138.3，136.6，136.4，134.3，132.3，131.3，130.1，128.9，129.7，128.4，127.8，127.3，122.0，115.7，112.9，107.9，69.8，64.4，38.8，31.5，27.8。
6-[3-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline synthetic
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-6-[3-(benzylthio) phenoxy group]-1,2,3,4 tetrahydrochysenes-naphthalene 14g (34.6mmol), right-toluenesulphonic acids 4.4g (23.2mmol), acetone 200mL, get faint yellow solid compound 6-[3-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline 8.0g, productive rate 64%;
mp?179-181℃； 1H?NMR(400MHz，CDCl 3)δ：7.33-7.42(m，5H，5×-ArH)，7.29(s，1H，-ArH)，7.21-7.27(m，2H，2×-ArH)，7.07(t，1H，J＝8.0Hz，-ArH)，6.94-6.98(m，2H，2×-ArH)，6.86-6.89(m，1H，-ArH)，5.02(s，2H，-OCH 2-)，3.57(s，2H，-CH 2-)，3.00(t，2H，J＝6.8Hz，-CH 2-)，2.54(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：209.9，159.2，137.7，137.4，136.5，133.3，132.7，130.8，130.3，129.9，129.1，128.5，128.0，127.4，122.9，116.7，113.4，70.0，44.7，37.8，28.1。
3 ', 4 '-dihydro-6 '-[3-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone is got 6-[3-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline 10g (27.8mmo), potassium cyanide 2.25g (34.6mmol), volatile salt 25g (260.4mmol), water 50mL, ethanol 150mL gets white solid 3 ', 4 '-dihydro-6 '-[3-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 8g, productive rate 67%;
mp?357-359℃； 1H?NMR(400MHz，DMSO)δ：10.3(brs，1H，-NH-)，8.25(brs，1H，-NH-)，7.36-7.42(m，4H，4×-ArH)，7.30-7.34(m，1H，-ArH)，7.25(t，1H，J＝8.0Hz，-ArH)，7.19(s，1H，-ArH)，7.10-7.15(m，2H，2×-ArH)，6.90-6.93(m，1H，-ArH)，6.86-6.87(m，2H，2×-ArH)，6.81-6.83(m，2H，2×-ArH)，5.07(s，2H，-OCH 2-)，3.10(d，1H，J＝17.2Hz，-CH-)，2.86-2.89(m，2H，-CH 2-)，2.78(d，1H，J＝17.2Hz，-CH-)，1.90-1.95(m，1H，-CH-)，1.78-1.81(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.4，158.8，156.7，137.3，136.7，136.5，133.1，132.1，130.5，130.3，129.6，128.4，127.8，127.7，121.7，115.7，113.2，69.3，60.6，36.6，29.8，24.6。
2-urea groups-6-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-6 '-[3-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7.0g (16.3mmol), sodium hydroxide 10g (250mmol), water 100mL, DMSO 100mL, white solid 2-urea groups-6-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 6.5g, productive rate 87%;
mp?370-372℃； 1H?NMR(400MHz，DMSO)δ：7.32-7.41(m，5H，5×-ArH)，7.25(t，1H，J＝8.0Hz，-ArH)，7.18(s，1H，-ArH)，7.14(s，2H，2×-ArH)，6.91(d，1H，J＝8.0Hz，-ArH)，6.87(s，1H，-ArH)，6.81(d，1H，J＝8.0Hz，-ArH)，5.07(s，2H，-CH 2-)，3.30(d，1H，J＝17.2Hz，-ArH)，2.88(d，1H，J＝17.2Hz，-ArH)，2.76-2.79(m，2H，-CH 2-)，2.09-2.17(m，1H，-CH-)，1.93-1.98(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：172.3，158.8，137.2，136.7，133.3，131.9，130.3，130.0，129.6，128.4，127.8，127.7，121.7，115.7，113.2，69.3，57.5，34.8，28.8，24.7。
2-amino-6-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride 027028 thereof synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-6-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 6g (14.8mmol), lithium aluminum hydride 1.2g (31.6mmol), tetrahydrofuran (THF) 150mL, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for amino 6-[3-(benzyloxy) thiophenyl of crude product 2-]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the solid that added diethyl ether is separated out, filter dry amino 6-[3-(benzyloxy) thiophenyl of white solid 2-]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 4.0g, productive rate 67%;
Mp 248-250 ℃; 1H NMR (400MHz, DMSO) δ: 8.10 (brs, 3H ,-NH 3 +), 7.30-7.40 (m, 5H, 5 *-ArH), 7.24 (t, 1H, J=8.0Hz ,-ArH), 7.17 (s, 1H ,-ArH), 7.12 (s, 2H, 2 *-ArH), 6.90 (dd, 1H, J=8.4Hz, J=2.0Hz ,-ArH), 6.84 (s, 1H ,-ArH), 6.79 (d, 1H, J=8.0Hz ,-ArH), 5.53 (s, 1H ,-OH), 5.05 (s, 2H ,-OCH 2-), 3.37 (s, 2H ,-CH 2-), 2.89 (s, 2H ,-CH 2-), 2.74-2.79 (m, 2H ,-CH 2-), 1.90 (t, 2H, J=6.8Hz ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 158.8,137.1,136.7,136.3,132.7,131.9,130.8,130.5,130.3,129.6,128.4,127.8,127.6,121.8,115.7,113.3,69.3,63.1,55.6,33.8,27.1,24.5; Mass spectrum ESI-MS:(C 24H 25NO 2S.HCl) (M ++ 1) 177; Infrared spectra IR (KBr) vcm -1: 3361,3034,2929,2364,1589,1450,1290,1232,1047,881,775,735,694.
The method for splitting of FC-028 is as follows:
Figure G2008100516876D0000491
Experimentation is with the method for splitting of 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate, get racemic mixture [(±) FC-027] 3g (7.7mmol), S-(+)-amygdalic acid 1.4g (9.2mmol), methyl alcohol 20mL, get levorotatory compound [(-)-FC-028] 0.5g, [α] D 20=-5.4 ° (c=1.0, methyl alcohol) and dextrorotatory compound [(+)-FC-028] 0.4g, [α] D 20=+5.5 ° (c=1.0, methyl alcohol).
Embodiment 15:
The synthetic method of 2-amino-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-029) and hydrochloride (FC-030) (hereinafter to be referred as FC-029, FC-030) thereof is as follows:
Figure G2008100516876D0000492
Synthesizing of 3-oxygen base-toluylic acid in positive heptan
Experimentation is with 4-oxygen base-toluylic acid in positive heptan, between getting-hydroxyl phenylacetic acid 5g (32.9mmol), positive heptyl bromide 11.7g (65.8mmol), salt of wormwood 9.0g (65.8mmol), ethanol 100mL, oily compound 3-oxygen in positive heptan base-toluylic acid 5.5g, productive rate 67%;
1H?NMR(400MHz，DMSO)δ：12.2(s，1H，-COOH)，7.19(t，1H，J＝8.0Hz，-ArH)，6.78-6.81(m，3H，3×-ArH)，3.92(t，2H，J＝6.8Hz，-CH 2-O)，3.51(s，2H，-CH 2-)，1.67-1.71(m，2H，-CH 2-)，1.28-1.42(m，8H，4×-CH 2-)，0.87(t，3H，J＝6.8Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：172.5，158.6，136.4，129.2，121.4，115.6，112.4，67.3，31.2，28.7，28.4，25.5，22.0，13.9。
Synthesizing of 7-oxygen in positive heptan base-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-bromo-2-Tetralone an intermediate of Sertraline, get 3-oxygen in positive heptan base-toluylic acid 20g (80.0mmol), 1,2-ethylene dichloride 240mL, thionyl chloride 21mL (296mmol), aluminum trichloride (anhydrous) 28g (209mmol), methylene dichloride 400mL, get white solid compound 7-oxygen in positive heptan base-2-Tetralone an intermediate of Sertraline 10g, productive rate 48%;
mp?80-82℃； 1H?NMR(400MHz，CDCl 3)δ：7.12(d，1H，J＝8.4Hz，-ArH)，6.75(dd，1H，J＝8.4Hz，J＝2.4Hz，-ArH)，6.66(d，1H，J＝2.0Hz，-ArH)，3.93(t，2H，J＝6.8Hz，-CH 2-O)，3.54(s，2H，-CH 2-)，2.99(t，2H，J＝6.8Hz，-CH 2-)，2.54(t，2H，J＝6.8Hz，-CH 2-)，1.73-1.78(m，2H，-CH 2-)，1.37-1.46(m，2H，-CH 2-)，1.31-1.36(m，6H，3×-CH 2-)，0.89(3H，J＝6.8Hz，-CH 3)； 13C?NMR(100MHz，CDCl 3)δ：210.4，157.9，134.3，128.3，113.9，112.7，67.9，45.0，38.4，31.6，29.1，28.9，27.3，25.8，22.5，13.9。
3 ', 4 '-dihydro-7 '-positive oxygen base-spiral shell in heptan [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-oxygen in positive heptan base-2-Tetralone an intermediate of Sertraline 5.5g (21.1mmol), potassium cyanide 1.65g (25.4mmol), volatile salt 18.5g (192.7mmol), 50% ethanol 140mL, get white solid compound 3 ', 4 '-dihydro-7 '-positive oxygen base-spiral shell in heptan [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 3.2g, productive rate 46%;
mp?316-318℃； 1H?NMR(400MHz，DMSO)δ：10.69(s，1H，-NH-)，8.28(s，1H，-NH-)，7.01(d，1H，J＝8.0Hz，-ArH)，6.71(dd，1H，J＝8.0Hz，J＝4.0Hz，-ArH)，6.65(s，1H，-ArH)，3.89(t，2H，J＝6.4Hz，-CH 2-O)，3.06(d，1H，J＝16.8Hz，-CH-)，2.81-2.84(m，2H，-CH 2-)，2.71(d，1H，J＝16.8Hz，-CH-)，1.86-1.92(m，1H，-CH-)，1.76-1.79(m，1H，-CH-)，1.64-1.70(m，2H，-CH 2-)，1.27-1.38(m，8H，4×-CH 2-)，0.86(t，3H，J＝6.8Hz，-CH 3)； 13C?NMR(100MHz，DMSO)δ：178.2，156.8，156.3，133.6，129.4，126.6，114.1，112.8，67.3，60.7，37.1，31.2，30.3，28.7，28.4，25.5，23.8，22.0，13.9。
Synthesizing of 2-urea groups-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-positive oxygen base-spiral shell [tetrahydroglyoxaline-4 in heptan, 2 ' (1 ' H)-naphthalene]-2,5-diketone 7g (21.2mmol), sodium hydroxide 20g (500mmol), water 200mL, get white solid compound 2-urea groups-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
mp?326-328℃； 1H?NMR(400MHz，DMSO)δ：6.96(d，1H，J＝8.4Hz，-ArH)，6.45(d，1H，J＝8.0Hz，-ArH)，6.62(s，1H，-ArH)，6.20(s，1H，-NH-)，5.45(s，2H，-NH 2)，3.89(t，2H，J＝6.4Hz，-CH 2-O)，3.11(d，1H，J＝16.8Hz，-CH-)，2.92(d，1H，J＝16.8Hz，-CH-)，2.65(s，2H，-CH 2-)，2.23-2.26(m，1H，-CH-)，1.80-1.87(m，1H，-CH-)，1.65-1.69(m，2H，-CH 2-)，1.27-1.38(m，8H，4×-CH 2-)，0.85-0.87(m?3H，-CH 3)； 13C?NMR(100MHz，DMSO)δ：175.9，158.3，156.7，134.9，129.1，126.7，114.4，112.4，67.2，56.1，37.4，31.2，29.2，28.7，28.4，25.5，24.0，22.0，13.9。
Synthesizing of 2-amino-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (5.7mmol), lithium aluminum hydride 0.7g (18.4mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction, be spin-dried for solvent and get crude product 2-urea groups-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-7-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 27% of getting;
Mp 218-220 ℃; 1H NMR (400MHz, DMSO) δ: 8.12 (s, 3H ,-NH 3 +), 7.00 (d, 1H, J=8.4Hz ,-ArH), 6.716.71 (dd, 1H, J=8.4Hz, J=2.8Hz ,-ArH), 6.65 (d, 1H, J=2.4Hz ,-ArH), 5.53 (s, 1H ,-OH), 3.89 (t, 2H, J=6.4Hz ,-CH 2-O), 3.42 (s, 2H ,-CH 2-), 2.86 (s, 2H ,-CH 2-) 2.68-2.74 (m, 2H ,-CH 2-), 1.87-1.93 (m, 2H ,-CH 2-), 1.63-1.70 (m, 2H ,-CH 2-), 1.27-1.38 (m, 8H, 4 *-CH 2-), 0.86 (t, 3H, J=6.8Hz ,-CH 3); 13C NMR (100MHz, DMSO) δ: 156.9,133.5,129.4,126.2,114.2,113.1,67.3,62.7,55.7,34.3,31.2,28.7,28.4,27.5,25.5,23.8,22.0,13.9; Mass spectrum ESI-MS:(C 18H 29NO 2.HCl) (M ++ 1) 291; Infrared spectra IR (KBr) vcm -1: 3375,3018,2931,2870,2362,1610,1506,1468,1238,1057,1007,837,818.
Embodiment 16:
The synthetic method of 2-amino-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-031) and hydrochloride (FC-032) (hereinafter to be referred as FC-031, FC-032) thereof is as follows:
Figure G2008100516876D0000521
Synthesizing of 2-(1, the 3-dioxolane)-7-bromo-1,2,3,4-tetrahydrochysene-naphthalene
Get 7-bromo-2-Tetralone an intermediate of Sertraline 10g (44.4mmol), ethylene glycol 4g (66.7mmol), tosic acid 0.5g (2.6mmol), hexanaphthene 100mL, heating reflux reaction 4h in the three-necked bottle of water trap is housed, cooling, add saturated sodium bicarbonate and be washed till neutrality, ethyl acetate extraction, anhydrous magnesium sulfate drying is spin-dried for solvent silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 10), get faint yellow solid compound 2-(1, the 3-dioxolane)-and 7-bromo-1,2,3,4-tetrahydrochysene-naphthalene 9.8g, productive rate 82%
Synthesizing of 2-(1, the 3-dioxolane)-7-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene; get phenol 4.2g (44.8mmol), 2-(1, the 3-dioxolane)-7-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.3mmol); salt of wormwood 12.4g (106.6mmol); Red copper oxide 7.2g (44.8mmol), pyridine 200mL, faint yellow oily compound 2-(1; the 3-dioxolane)-7-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene 8.5g, productive rate 81%;
1H?NMR(400MHz，CDCl 3)δ：7.30-7.34(m，2H，2×-ArH)，7.06-7.11(m，2H，2×-ArH)，7.00(d，2H，J＝8.0Hz，2×-ArH)，6.81(dd，1H，J＝8.4Hz，J＝2.4Hz，-ArH)，6.71(d，1H，J＝2.0Hz，-ArH)，4.02-4.03(m，4H，2×-CH 2-)，2.94-2.99(m，4H，2×-CH 2-)，1.97(t，2H，J＝2.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：157.3，154.6，135.9，129.9，129.3，129.2，122.4，119.0，118.1，116.8，107.6，64.0，38.8，31.5，27.0。
Synthesizing of 7-phenoxy group-2-Tetralone an intermediate of Sertraline
Experimentation is got 2-(1, the 3-dioxolane)-7-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene 9g (31.9mmol) with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, right-toluenesulphonic acids 3.7g (21.3mmol), acetone 300mL gets white solid compound 7-phenoxy group-2-Tetralone an intermediate of Sertraline 7g, productive rate 86%;
mp?33-35℃； 1H?NMR(400MHz，CDCl 3)δ：7.23-7.27(m，2H，2×-ArH)，7.10(d，1H，J＝8.4Hz，-ArH)，7.0-7.03(m，1H，-ArH)，6.91(d，2H，J＝7.6Hz，2×-ArH)，6.80(dd，1H，J＝8.4Hz，J＝2.4Hz，-ArH)，6.70(d，1H，J＝2.4Hz，-ArH)，3.45(s，2H，-CH 2-)，2.92-2.98(m，2H，-CH2-)，2.43-2.49(m，2H，-CH2-)； 13C?NMR(100MHz，CDCl 3)δ：210.0，157.1，155.9，134.5，132.0，129.6，128.7，123.1，118.6，118.4，117.2，44.8，38.1，27.5。
3 ', 4 '-dihydro-7 '-phenoxy group-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-phenoxy group-2-Tetralone an intermediate of Sertraline 7g (29.4mmol), potassium cyanide 2.3g (35.3mmol), volatile salt 25.5g (264.6mmol), 50% ethanol 180mL, get white solid compound 3 ', 4 '-dihydro-7 '-phenoxy group-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7g, productive rate 77%;
mp?322-325℃； 1H?NMR(400MHz，DMSO)δ：10.7(s，1H，-NH-)，8.29(s，1H，-NH-)，7.36(t，2H，J＝8.0Hz，2×-ArH)，7.14(t，1H，J＝8.0Hz，-ArH)，7.10(d，1H，J＝7.2Hz，-ArH)，6.9(d，2H，J＝8.0Hz，2×-ArH)，6.79-6.81(m，2H，2×-ArH)，3.08(d，1H，J＝16.8Hz，-CH-)，2.87-2.90(m，2H，-CH 2-)，2.74(d，1H，J＝16.8Hz，-CH-)，1.91-1.99(m，1H，-CH-)，1.80-1.83(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，157.1，156.3，154.3，134.5，130.2，130.0，129.9，123.0，119.1，118.0，116.9，60.5，36.9，30.1，24.1。
Synthesizing of 2-urea groups-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-phenoxy group-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7g (22.7mmol), sodium hydroxide 20g (500mmol), water 200mL, get white solid compound 2-urea groups-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
mp324-326℃； 1H?NMR(400MHz，DMSO)δ：12.28(s，1H，-COOH)，7.35-7.39(m，2H，2×-ArH)，7.09-7.13(m，2H，2×-ArH)，6.95-6.98(m，2H，2×-ArH)，6.73-6.76(m，2H，2×-ArH)，6.25(s，1H，-NH-)，5.46(s，2H，-NH 2)，3.13(d，1H，J＝17.2Hz，-CH-)，2.93(d，1H，J＝17.2Hz，-CH-)，2.73(m，2H，-CH 2-)，2.26-2.29(m，1H，-CH-)，1.84-1.92(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.9，158.3，157.0，154.3，135.8，130.2，129.9，129.8，123.0，119.2，118.2，116.4，55.9，37.2，29.0，24.3。
Synthesizing of 2-amino-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (6.1mmol), lithium aluminum hydride 0.7g (18.4mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h adds 1N NaOH 100mL, ethyl acetate extraction under the ice bath, be spin-dried for solvent and get crude product 2-urea groups-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-7-phenoxy group-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 24% of getting;
Mp 222-224 ℃; 1H NMR (400MHz, DMSO) δ: 7.99 (brs, 3H ,-NH 3 +), 7.38 (t, 2H, J=8.0Hz, 2 *-ArH), 7.12 (m, 2H, 2 *-ArH), 6.97 (d, 2H, J=8.8Hz, 2 *-ArH), 6.82 (m, 2H, 2 *-ArH), 5.55 (s, 1H ,-OH), 3.44 (s, 2H ,-CH 2-), 2.74-2.91 (m, 4H, 2 *-CH 2-), 1.88-1.95 (m, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 156.9,154.5,134.3,130.0,129.9,129.8,123.1,119.0,118.2,117.0,62.8,55.6,34.0,27.4,24.0; Mass spectrum ESI-MS:(C 17H 19NO 2.HCl) (M ++ 1) 269; Infrared spectra IR (KBr) vcm -1: 3367,3024,2916,1591,1486,1259,1055,769,690.
Embodiment 17:
The synthetic method of 2-amino-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-033) and hydrochloride (FC-034) (hereinafter to be referred as FC-033, FC-034) thereof is as follows:
Figure G2008100516876D0000541
Synthesizing of 2-(1, the 3-dioxolane)-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-naphthalene
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get right-methoxyphenol 9.3g (74.6mmol), 2-(1, the 3-dioxolane)-7-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.3mmol), salt of wormwood 20g (149.2mmol), Red copper oxide 11.9g (74.6mmol), pyridine 200mL gets faint yellow oily compound 2-(1, the 3-dioxolane)-and 7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-naphthalene 8.5g, productive rate 73%;
1H?NMR(400MHz，CDCl 3)δ：7.04(d，1H，J＝8.0Hz，-ArH)，6.93-6.96(m，2H，2×-ArH)，6.84-6.88(m，2H，2×-ArH)，6.73(dd，1H，J＝8.4Hz，J＝2.4Hz，-ArH)，6.62(d，1H，J＝2.4Hz，-ArH)，4.01-4.03(m，4H，2×-CH 2-)，3.79(s，3H，-OCH 3)，2.93-2.96(m，4H，2×-CH 2-)，1.95(t，2H，J＝6.8Hz，-CH 2-)； 13CNMR(100MHz，CDCl 3)δ：156.4，155.6，150.5，135.8，129.5，129.3，120.4，117.9，115.9，114.7，108.0，64.4，55.5，39.2，31.8，27.2。
Synthesizing of 7-(4-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-naphthalene 9g (28.8mmol), right-toluenesulphonic acids 3.3g (19.2mmol), acetone 300mL, get white solid compound 7-(4-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline 7g, productive rate 90%;
mp?87-89℃； 1H?NMR(400MHz，CDCl 3)δ：7.16(d，1H，J＝8.0Hz，-ArH)，6.96-6.99(m，2H，2×-ArH)，6.87-6.92(m，2H，2×-ArH)，6.81(dd，1H，J＝8.4Hz，J＝2.4Hz，-ArH)，6.72(s，1H，-ArH)，3.82(s，3H，-OCH 3)，3.53(s，2H，-CH 2-)，3.04(t，2H，J＝6.8Hz，-CH 2-)，2.55(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：210.0，157.3，155.8，149.9，134.7，130.5，128.6，120.6，117.1，115.9，114.7，55.5，44.9，38.2，27.5。
3 ', 4 '-dihydro-7 '-(4-methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-(4-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline 7g (26.2mmol), potassium cyanide 2.0g (31.3mmol), volatile salt 22.6g (235.8mmol), 50% ethanol 180mL, get white solid compound 3 ', 4 '-dihydro-7 '-(4-methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7g, productive rate 79%;
mp?333-335℃； 1H?NMR(400MHz，DMSO)δ：10.68(s，1H，-NH-)，8.27(s，1H，-NH-)，7.10(d，1H，J＝8.0Hz，-ArH)，6.94(s，4H，4×-ArH)，6.69-6.73(m，2H，2×-ArH)，3.73(s，3H，-OCH 3)，3.06(d，1H，J＝16.0Hz，-CH-)，2.84-2.87(m，2H，-CH 2-)，2.72(d，1H，J＝16.0Hz，-CH-)，1.83-1.95(m，1H，-CH-)，1.78-1.83(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，156.3，155.8，155.4，149.8，134.3，129.8，129.2，120.2，117.6，115.7，114.9，60.6，55.4，36.9，30.1，24.0。
Synthesizing of 2-urea groups-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-(4-methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7g (20.7mmol), sodium hydroxide 20g (500mmol), water 200ml, get white solid compound 2-urea groups-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
mp?334-336℃； 1H?NMR(400MHz，DMSO)δ：12.3(s，1H，-COOH)，7.05(d，1H，J＝8.0Hz，-ArH)，6.92-6.97(m，4H，4×-ArH)，6.65-6.67(m，2H，2×-ArH)，6.25(s，1H，-NH)，5.46(s，2H，-NH 2)，3.74(s，3H，-OCH 3)，3.11(d，1H，J＝20.0Hz，-CH-)，2.90(d，1H，J＝16.0Hz，-CH-)，2.69-2.72(s，2H，-CH 2-)，2.24-2.28(m，1H，-CH-)，1.84-1.90(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.9，158.4，155.8，155.4，149.7，135.6，129.6，129.2，120.4，117.8，115.1，115.0，56.1，55.4，37.3，29.2，24.2。
2-amino-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride FC-033034's thereof is synthetic
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (5.6mmol), lithium aluminum hydride 0.6g (16.8mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction, be spin-dried for solvent and get crude product 2-urea groups-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether, be spin-dried for solvent and get crude product 2-amino-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the adularescent solid that adds diethyl ether is separated out, filter dry white solid 2-amino-7-(4-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.5g, the productive rate 26% of getting;
Mp 198-200 ℃; 1H NMR (400MHz, DMSO) δ: 8.20 (brs, 3H ,-NH 3 +), 7.08 (d, 1H, J=8.4Hz ,-ArH.), 6.93-6.97 (m, 4H, 4 *-ArH), 6.72 (dd, 1H, J=8.0Hz, J=2.4Hz ,-ArH), 6.66-6.67 (m, 1H ,-ArH), 5.56 (brs, 1H ,-OH), 3.74 (s, 3H ,-OCH 3), 3.43 (s, 2H ,-CH 2-), 2.85 (d, 2H, J=4.0Hz ,-CH 2-), 2.72-2.86 (m, 2H ,-CH 2-), 1.93-1.94 (m, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 156.0,155.4,149.6,134.1,129.9,128.8,120.4,117.6,115.8,115.0,62.8,55.7,55.4,34.1,27.4,24.0; Mass spectrum ESI-MS:(C 18H 21NO 3.HCl) (M ++ 1) 299; Infrared spectra IR (KBr) vcm -1: 3383,3041,2929,2634,2540,1614,1497,1238,1207,1036,833,769.
Embodiment 18:
2-amino-7-[4-(benzyloxy) phenoxy group]-1,2,3, the synthetic method of 4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-035) and hydrochloride (FC-036) (hereinafter to be referred as FC-035, FC-036) thereof is as follows:
Figure G2008100516876D0000571
Synthesizing of 4-benzyloxy phenol
Get to biphenol 20g (0.18mol) salt of wormwood 50g (0.36mol), dehydrated alcohol 300mL, reflux slowly drips the mixing solutions of 20g bromotoluene (0.12mol) and 60mL dehydrated alcohol, dropwises in the 2h, cooling is filtered, and steams and removes ethanol, add water and transfer pH=2 with HCl, ethyl acetate extraction concentrates silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 5), get brown liquid 4-benzyloxy phenol 28g, 70%;
2-(1, the 3-dioxolane)-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-naphthalene synthetic
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get 4-benzyloxy phenol 11.0g (55.0mmol), 2-(1, the 3-dioxolane)-7-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.3mmol), salt of wormwood 15g (108.7mmol), Red copper oxide 8.0g (55.6mmol), pyridine 250mL gets faint yellow oily compound 2-(1, the 3-dioxolane)-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-naphthalene 10g, productive rate 70%;
1H?NMR(400MHz，CDCl 3)δ：7.44(d，2H，J＝7.2Hz，2×-ArH)，7.40(t，2H，J＝7.2Hz，2×-ArH)，7.32-7.35(m，1H，-ArH)，7.05(d，1H，J＝8.4Hz，-ArH)，6.93-6.97(m，4H，4×-ArH)，6.75(dd，1H，J＝2.4Hz，J＝8.4Hz，-ArH)，6.64(d，1H，J＝2.4Hz，-ArH)，5.05(s，2H，-CH 2-O-)，4.03(s，4H，2×-CH 2-)，2.94-2.97(m，4H，2×-CH 2-)，1.96(t，2H，J＝6.4Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：156.2，154.7，150.7，136.9，135.8，129.5，129.4，128.5，127.8，127.4，120.3，118.1，116.0，115.7，108.0，70.4，64.4，39.1，31.8，27.2。
7-[4-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline synthetic
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-naphthalene 10g (25.8mmol), right-toluenesulphonic acids 3.0g (17.2mmol), acetone 200mL, get faint yellow solid compound 7-[4-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline 6.0g, productive rate 68%;
mp?128-130℃； 1H?NMR(400MHz，CDCl 3)δ：7.44(d，2H，J＝6.8Hz，2×-ArH)，7.38-7.42(m，2H，2×-ArH)，7.32-7.35(m，1H，-ArH)，7.15(d，1H，J＝8.4Hz，-ArH)，6.94-6.96(m，4H，4×-ArH)，6.81(dd，1H，J＝2.4Hz，J＝8.4Hz，-ArH)，6.71(d，1H，J＝2.4Hz，-ArH)，5.06(s，2H，-CH 2-O-)，3.52(s，2H，-CH 2-)，3.03(t，2H，J＝6.8Hz，-CH 2-)，2.55(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：210.2，157.3，155.1，150.4，136.9，134.8，130.7，128.7，128.6，128.0，127.5，120.6，117.3，116.2，115.9，115.8，70.6，45.1，38.4，27.6。
3 ', 4 '-dihydro-7 '-[4-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-[4-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline 5.5g (16.0mmol), potassium cyanide 1.3g (20.0mmol), volatile salt 13.8g (143.8mmol), 50% ethanol 110mL, get white solid compound 3 ', 4 '-dihydro-7 '-[4-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 4.0g, productive rate 63%;
mp?370-372℃； 1H?NMR(400MHz，DMSO)δ：10.66(s，1H，-NH-)，8.26(s，1H，-NH-)，7.43(d，2H，J＝6.8Hz，2×-ArH)，7.38(t，2H，J＝7.2Hz，2×-ArH)，7.29-7.33(m，1H，-ArH)，7.08(d，1H，J＝8.4Hz，-ArH)，7.00(d，2H，J＝9.2Hz，2×-ArH)，6.93(d，2H，J＝8.8Hz，2×-ArH)，6.68-6.72(m，2H，2×-ArH)，5.06(s，2H，-CH 2-O-)，3.05(d，1H，J＝16.0Hz，-CH-)，2.73(s，2H，-CH 2-)，2.71(d，1H，J＝16.0Hz，-CH-)，1.88-1.95(m，1H，-CH-)，1.77-1.80(m，1H，-CH-)； 13CNMR(100MHz，DMSO)δ：178.2，156.4，155.7，154.5，150.2，137.1，134.4，129.9，129.4，128.4，127.8，127.7，120.2，117.8，116.0，115.9，69.7，60.6，36.9，30.2，24.1。
2-amino-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthoic acid synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-[4-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 4.0g (10.0mmol), sodium hydroxide 10.0g (250mmol), water 100mL, white solid compound 2-amino-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 3.2g, productive rate 82%;
mp?370-375℃； 1H?NMR(400MHz，DMSO)δ：7.45(d，2H，J＝7.2Hz，2×-ArH)，7.38(t，2H，J＝7.2Hz，2×-ArH)，7.31-7.35(m，1H，-ArH)，7.07(d，1H，J＝8.0Hz，-ArH)，7.07(d，2H，J＝9.2Hz，2×-ArH)，6.94(d，2H，J＝9.2Hz，2×-ArH)，6.69-6.72(m，2H，2×-ArH)，5.07(s，2H，-CH 2-O-)，3.05(d，1H，J＝17.2Hz，-CH-)，2.85(d，1H，J＝17.2Hz，-CH-)，2.76(t，2H，J＝6.0Hz，-CH 2-)，2.08-2.15(m，1H，-CH-)，1.94-2.00(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：172.4，155.8，154.5，150.0，137.0，134.6，129.7，129.2，128.4，127.8，127.7，120.2，117.4，115.9，115.5，69.6，57.5，35.1，29.3，24.2。
2-amino-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (5.1mmol), lithium aluminum hydride 0.59g (15.3mmol), tetrahydrofuran (THF) 50mL, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the solid that added diethyl ether is separated out, filter dry white solid 2-amino-7-[4-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, productive rate 25%;
Mp 252-254 ℃; 1H NMR (400MHz, DMSO) δ: 8.25 (brs, 3H ,-NH 3 +), 7.45 (d, 2H, J=7.2Hz, 2 *-ArH), 7.38 (t, 2H, J=7.2Hz, 2 *-ArH), 7.33-7.35 (m, 1H ,-ArH), 7.10 (d, 1H, J=8.4Hz ,-ArH), 7.02-7.04 (m, 2H, 2 *-ArH), 6.94-6.97 (m, 2H, 2 *-ArH), 6.73 (dd, 1H, J=2.4Hz, J=8.4Hz,-ArH), 6.69 (d, 1H, J=2.4Hz ,-ArH), 5.54 (t, 1H, J=5.2Hz ,-OH), 5.08 (s, 2H ,-CH 2-O-), 3.43 (d, 2H, J=4.8Hz ,-CH 2-), 2.84 (s, 2H ,-CH 2-), 2.75-2.76 (m, 2H ,-CH 2-), 1.91 (m, 2H ,-CH 2-); 13CNMR (100MHz, DMSO) δ: 155.9,154.5,149.9,137.0,134.0,129.9,128.9,128.4,127.8,127.6,120.3,117.7,115.9,69.6,62.9,55.6,34.1,27.4,23.9; Mass spectrum ESI-MS:(C 24H 25NO 3.HCl) (M ++ 1); Infrared spectra IR (KBr) vcm -1: 3392,3153,3034,2929,2874,1614,1506,1240,1065,1014,835,744,696.
Embodiment 19:
The synthetic method of 2-amino-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-037) and hydrochloride (FC-038) (hereinafter to be referred as FC-037, FC-038) thereof is as follows:
Figure G2008100516876D0000601
Synthesizing of 7-phenyl-2-Tetralone an intermediate of Sertraline
Experimentation is with 6-phenyl-2-Tetralone an intermediate of Sertraline; get phenylo boric acid 4.8g (39.3mmol); 7-bromo-2-Tetralone an intermediate of Sertraline 6g (26.8mmol); palladium 0.12g (0.5mmol), thricyclohexyl phosphorus 0.48g (1.7mmol), and three water potassiumphosphate 19.2g (72.2mmol); toluene 120mL; water 25mL get faint yellow solid compound 7-phenyl-2-Tetralone an intermediate of Sertraline 5.6g, productive rate 93%;
mp?85-88℃； 1H?NMR(400MHz，CDCl 3)δ：7.57(d，2H，J＝7.6Hz，2×-ArH)，7.44(t，3H，J＝7.6Hz，3×-ArH)，7.35-7.37(m，2H，2×ArH)，7.31(d，1H，J＝7.6Hz，-ArH)，3.66(s，2H，-CH 2-)，3.12(t，2H，J＝6.8Hz，-CH 2-)，2.60(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：210.4，140.5，139.9，135.6，133.6，128.7，127.9，127.2，126.9，126.8，125.5，45.0，38.1，27.9。
3 ', 4 '-dihydro-7 '-phenyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-phenyl-2-Tetralone an intermediate of Sertraline 6.5g (29.3mmol), potassium cyanide 2.5g (38.5mmol), volatile salt 25.3g (263.5mmol), 50% ethanol 190mL, get white solid compound 3 ', 4 '-dihydro-7 '-phenyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 6.0g, productive rate 70%;
mp?326-328℃； 1H?NMR(400MHz，DMSO)δ：10.72(s，1H，-NH-)，8.34(s，1H，-NH-)，7.62(d，2H，J＝8.0Hz，2×-ArH)，7.40-7.46(m，4H，4×-ArH)，7.34(t，1H，J＝8.0Hz，-ArH)，7.22(d，1H，J＝8.0Hz，-ArH)，3.18(d，1H，J＝20.0Hz，-CH-)，2.93-2.94(m，2H，-CH 2-)，2.86(d，1H，J＝16.0Hz，-CH-)，1.98-2.02(m，1H，-CH-)，1.83-1.86(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，156.8，140.0，137.9，134.2，133.2，129.1，128.8，127.1，126.4，124.4，60.7，38.8，30.0，24.4。
Synthesizing of 2-urea groups-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-phenyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 6g (20.5mmol), sodium hydroxide 10g (250mmol), water 200mL, get white solid compound 2-urea groups-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 4.5g, productive rate 81%;
mp?385-387℃； 1H?NMR(400MHz，DMSO)δ：7.60(d，2H，J＝7.2Hz，2×-ArH)，7.43(t，2H，J＝7.6Hz，2×-ArH)，7.14-7.35(m，3H，3×-ArH)，6.19(s，1H，-NH-)，5.55(s，2H，-NH 2)，3.14(s，2H，-CH 2-)，2.74-2.79(m，2H，-CH 2-)，2.31-2.34(m，1H，-CH-)，1.84-1.86(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.9，158.4，140.2，137.5，134.9，134.6，128.9，128.8，127.3，126.9，126.4，123.8，56.4，37.4，29.0，24.9。
Synthesizing of 2-amino-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2g (6.4mmol), lithium aluminum hydride 0.73g (19.2mmol), tetrahydrofuran (THF) 50mL, stirring at room reaction 36h adds 1N NaOH 100mL, ethyl acetate extraction under the ice bath, be spin-dried for solvent and get crude product 2-urea groups-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether is spin-dried for solvent and gets crude product 2-amino-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, and this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the adularescent solid that adds diethyl ether is separated out, and filters, dry white solid 2-amino-7-phenyl-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.6g, the productive rate 32% of getting;
Mp 263-265 ℃; 1H NMR (400MHz, DMSO) δ: 8.19 (brs, 1H ,-NH 3 +), 7.35 (d, 2H, J=7.6Hz, 2 *-ArH), 7.41-7.46 (m, 4H, 4 *-ArH), 7.34 (t, 1H, J=7.6Hz ,-ArH), 7.22 (d, 1H, J=8.0Hz ,-ArH), 3.48 (s, 2H ,-CH 2-), 2.99 (s, 2H ,-CH 2-), 2.81-2.89 (m, 2H ,-CH 2-), 1.94-2.01 (m, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 139.9,137.9,133.9,133.0,129.1,128.8,127.3,127.2,126.4,124.5,62.9,55.8,34.2,27.3,24.4; Mass spectrum ESI-MS:(C 17H 19NO.HCl) (M ++ 1): 253; Infrared spectra IR (KBr) vcm -1: 3433,3165,2918,2654,1605,1535,1485,1406,1061,764,690.
Embodiment 20:
The synthetic method of 2-amino-7-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-039) and hydrochloride (FC-040) thereof is as follows:
Synthesizing of 6-methoxyl group hexyl boric acid
Get l, 6-dibromo-hexane 50g (0.2mol), methyl alcohol 200mL, refluxing drips sodium methylate 9g down, reaction 2h, cooling adds water, extracted with diethyl ether, anhydrous magnesium sulfate drying, solvent evaporated column chromatography (developping agent: methylene dichloride: sherwood oil=1: 1), get weak yellow liquid 30g; Get magnesium ribbon 2.3g (0.96mmol), anhydrous diethyl ether 20mL, drip a small amount of 1-bromo-6-methoxyhexane 20g (0.1mmol) and 40mL anhydrous tetrahydro furan mixing solutions, and to wherein adding a small amount of iodine, question response takes place, slowly drip above-mentioned mixing solutions, reflux keeps that ether is little to boil, and dropwises in the 30min, reaction 2h, it is stand-by to make Grignard reagent; Get trimethyl borate 10g (0.96mmol), anhydrous tetrahydro furan 30mL is cooled to-65 ℃, logical N 2, slowly splash into above-mentioned Grignard reagent under the vigorous stirring, drip off and continue reaction 2h, ambient temperature overnight is used the 2NHCl acidifying, tells organic layer, the water layer extracted with diethyl ether merges organic layer, washing, add the water solvent evaporated, cooling is filtered, with an amount of toluene recrystallization, filter, sherwood oil is washed, get 6-methoxyl group hexyl boric acid 9g, productive rate 56%;
Synthesizing of 7-(6-methoxyl group hexyl)-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-normal-butyl-2-Tetralone an intermediate of Sertraline, get 6-methoxyl group hexyl boric acid 5g (31.3mmol), 7-bromo-2-Tetralone an intermediate of Sertraline 5g (22.3mmol), three water potassiumphosphate 21g (78.9mmol), palladium 0.25g (1.1mmol), thricyclohexyl phosphorus 0.7g (2.5mmol), toluene 100mL, water 5mL gets faint yellow oily compound 7-(6-methoxyl group hexyl)-2-Tetralone an intermediate of Sertraline 4.0g, productive rate 69%;
1H?NMR(400MHz，CDCl 3)δ：7.12(d，lH，J＝7.6Hz，-ArH)，7.01(d，1H，J＝7.6Hz，-ArH)，6.93(s，1H，-ArH)，3.55(t，2H，J＝6.4Hz，-CH 2-)，3.35(t，2H，J＝6.4Hz，O-CH 2-)，3.32(s，3H，-OCH 3)，3.02(t，2H，J＝6.8Hz，-CH 2-)，2.52-2.59(m，4H，2×-CH 2-)，1.53-1.62(m，4H，2×-CH 2-)，1.34-1.37(m，4H，2×-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：210.6，141.4，133.7，132.9，128.1，127.4，126.7，58.4，44.9，38.2，35.3，33.4，32.4，31.4，29.4，28.9，27.8，27.2，25.8。3 ', 4 '-dihydro-7 '-(6-methoxyl group hexyl)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-(6-methoxyl group hexyl)-2-Tetralone an intermediate of Sertraline 5g (19.2mmol), potassium cyanide 1.5g (23.1mmol), volatile salt 17g (177.1mmol), 50% ethanol 140mL, get white solid compound 3 ', 4 '-dihydro-7 '-(6-methoxyl group hexyl)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 3.0g, productive rate 48%;
mp??305-308℃； 1H?NMR(400MHz，DMSO)δ：7.02(d，1H，J＝8.0Hz，-ArH)，6.94(d，1H，J＝8.0Hz，-ArH)，6.90(s，1H，-ArH)，3.27(t，2H，J＝6.8Hz，O-CH 2-)，3.20(s，3H，O-CH 3)，3.07(d，1H，J＝16.8Hz，-CH-)，2.84-2.88(m，2H，-CH 2-)，2.72(d，1H，J＝16.8Hz，-CH-)，2.46-2.50(m，2H，-CH 2-)，1.89-1.94(m，1H，-CH-)，1.77-1.80(m，1H，-CH-)，1.44-1.53(m，4H，2×-CH 2-)，1.28-1.29(m，4H，2×-CH 2-)； 13C?NMR(100MHz，DMSO)δ：178.2，156.3，139.8，132.3，131.9，128.6，128.4，126.0，71.8，60.8，57.7，36.8，34.7，31.0，30.1，28.9，28.5，25.5，24.3。
Synthesizing of 2-amino-7-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-(6-methoxyl group hexyl)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 3.0g (9.0mmol), sodium hydroxide 10g (250mmol), water 100mL, get white solid compound 2-amino-7-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.2g, productive rate 79%;
mp?283-286℃； 1H?NMR(400MHz，DMSO)δ：6.99(s，1H，-ArH)，6.91-6.71(m，2H，2×-ArH)，3.28(t，2H，J＝6.4Hz，O-CH 2-)，3.20(s，3H，O-CH 3)，2.88(d，1H，J＝16.8Hz，-CH-)，2.77(s，2H，-CH 2-)，2.47-2.49(m，3H，-CH-，-CH 2-)，2.09-2.13(m，1H，-CH-)，1.97-2.01(m，1H，-CH-)，1.50-1.52(m，2H，-CH 2-)，1.47-1.48(m，2H，-CH 2-)，1.29(s，4H，2×-CH 2-)； 13C?NMR(100MHz，DMSO)δ：172.5，139.7，134.3，129.9，128.5，128.2，125.9，71.8，57.7，34.7，30.9，28.9，28.5，25.5，24.8。
Synthesizing of 2-amino-7-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-7-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (6.5mmol), lithium aluminum hydride 0.75g (19.7mmol), tetrahydrofuran (THF) 50mL, stirring at room reaction 12h adds water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-7-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the solid that added diethyl ether is separated out, filter dry white solid 2-amino-7-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.75g, the productive rate 36% of getting;
Mp 218-220 ℃; 1H NMR (400MHz, DMSO) δ: 8.17 (s, 3H ,-NH 3 +), 7.01 (d, 2H, J=7.6Hz, 2 *-ArH), 6.94 (d, 1H, J=7.6Hz ,-ArH), 5.52 (s, 1H ,-OH), 3.42 (d, 2H, J=3.6Hz ,-CH 2-), 3.27 (t, 2H, J=6.4Hz, O-CH 2-), 3.19 (s, 3H, O-CH 3), 2.88 (s, 2H ,-CH 2-), 2.74-2.76 (m, 2H ,-CH 2-), 2.50 (s, 2H ,-CH 2-), 1.92 (s, 2H ,-CH 2-), 1.46-1.52 (m, 4H, 2 *-CH 2-), 1.23-1.29 (m, 4H, 2 *-CH 2-); 13C NMR (100MHz, DMSO) δ: 139.9,132.1,131.6,128.8,128.4,126.2,71.8,62.8,57.7,55.8,34.6,34.0,30.9,28.9,28.5,27.4,25.4,24.3; Mass spectrum ESI-MS:(C 18H 29NO 2.HCl) (M ++ 1) 323; Infrared spectra IR (KBr) vcm -1: 3444,3273,2931,2854,1618,1578,1502,1120,1066,945,818.
Embodiment 21:
2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3, the synthetic method of 4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-041) and hydrochloride (FC-042) (hereinafter to be referred as FC-041, FC-042) thereof is as follows:
Figure G2008100516876D0000641
To synthesizing of benzyloxy thiophenol
1) gets p-hydroxybenzenyl sulfonate 30g, 250mL dehydrated alcohol, salt of wormwood 90g, reflux drips 44g bromotoluene and 50mL dehydrated alcohol mixing solutions, and 1.5h drips off, filtrate evaporate to dryness ethanol is filtered in cooling, add water and transfer pH=1, ethyl acetate extraction, anhydrous magnesium sulfate drying with hydrochloric acid, solvent evaporated adds methyl alcohol in refrigerator overnight, filters, get the white powder solid to benzyloxy Phenylsulfonic acid 38g, 75%
2) get to benzyloxy Phenylsulfonic acid 30g (0.11mol) DMF 200mL, dripping thionyl chloride 40g (0.33mol) under the ice bath, the reaction 0.5h after, room temperature reaction 2h, after the cooling with frozen water, ethyl acetate extraction, wash ester layer, anhydrous magnesium sulfate drying, solvent evaporated with saturated sodium bicarbonate solution, get the orange solid to benzyloxy benzene sulfonyl chloride 28g, 73%3) get to benzyloxy benzene sulfonyl chloride 20g (70.9mmol) acetic acid 200mL, stirring at room dissolving, add zinc powder 92.2g (1.4mol) in batches, backflow 1h, cooling adds water, ethyl acetate extraction, anhydrous magnesium sulfate drying, filter, concentrate solid 18g, 87.9%
2-(1, the 3-dioxolane)-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-naphthalene synthetic
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get to benzyloxy thiophenol 10g (46.3mmol) 2-(1, the 3-dioxolane)-7-bromo-1,2,3,4-tetrahydrochysene-naphthalene 14.2g (52.8mmol), salt of wormwood 23g (166.7mmol), Red copper oxide 16g (111.9mmol), DMF 150mL gets oily matter compound 2-(1, the 3-dioxolane)-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-naphthalene 14g, productive rate 75%;
1H?NMR(400MHz，CDCl 3)δ：7.39-7.42(m，4H，4×-ArH)，7.33-7.36(m，3H，3×-ArH)，7.00(s，2H，2-×ArH)，6.92-6.99(m，3H，3×-ArH)，5.06(s，2H，-OCH 2-)，4.00-4.02(m，4H，2×-CH 2-)，2.92-2.95(m，4H，2×-CH 2-)，1.93(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：158.4，136.5，135.3，134.4，134.1，133.5，129.9，129.0，128.4，127.8，127.3，125.7，115.6，107.8，69.8，64.3，38.8，31.5，27.5。
7-[4-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline synthetic
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-naphthalene 14g (34.6mmol), right-toluenesulphonic acids 4.4g (23.2mmol), acetone 200mL, get faint yellow solid compound 7-[4-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline 8.0g, productive rate 64%;
mp?192-194℃； 1H?NMR(400MHz，CDCl 3)δ：7.38-7.43(m，7H，7×-ArH)，7.08(d，1H，J＝15.2Hz，-ArH)，6.97(d，1H，J＝2.0Hz，-ArH)，6.96(d，3H，J＝2.4Hz，3×-ArH)，5.08(s，2H，-OCH 2-)，3.50(s，2H，-CH 2-)，3.01(t，2H，J＝6.8Hz，-CH 2-)，2.53(t，2H，J＝6.8Hz，-CH 2-)； 13CNMR(100MHz，CDCl 3)δ：209.6，158.7，136.3，134.6，134.4，134.0，128.4，128.1，127.8，127.2，126.9，124.6，115.6，69.8，44.6，37.7，27.6。
3 ', 4 '-dihydro-7 '-[4-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone is got 7-[4-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline 10g (27.8mmol), potassium cyanide 2.25g (34.6mmol), volatile salt 25g (260.4mmol), water 50mL, ethanol 150mL gets white solid compound 3 ', 4 '-dihydro-7 '-[4-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 8.0g, productive rate 67%;
mp?383-386℃； 1H?NMR??(400MHz，DMSO)δ：10.67(s，1H，-NH-)，8.24(s，1H，-NH-)，7.44(d，2H，J＝7.2Hz，2×-ArH)，7.37-7.41(m，2H，2×-ArH)，7.31-7.35(m，2H，2×-ArH)，7.05(m，3H，3×-ArH)，6.96(dd，1H，J＝1.6Hz，J＝8.0Hz，-ArH)，5.11(s，2H，-OCH 2-)，3.04(d，1H，J＝20.0Hz，-CH-)，2.85-2.87(m，2H，-CH 2-)，2.72(d，1H，J＝20.0Hz，-CH-)，1.88-1.93(m，1H，-CH-)，1.77-1.80(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.0，158.4，156.3，136.7，134.1，133.9，133.8，133.7，129.6，129.5，128.4，127.9，127.7，127.1，124.7，116.0，69.4，60.5，36.7，29.9，24.3。
2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-[4-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7.0g (16.3mmol), sodium hydroxide 10g (250mmol), water 100mL, DMSO 100mL, white solid compound 2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 6.5g, productive rate 87%;
mp?384-386℃； 1H?NMR(400MHz，DMSO)δ：7.33-7.45(m，7H，7×-ArH)，7.03-7.06(m，3H，3×-ArH)，6.97(s，1H，-ArH)，6.91(d，1H，J＝7.6Hz，-ArH)，5.11(s，2H，-OCH 2-)，3.22(d，1H，J＝17.2Hz，-CH-)，2.79(s，2H，-CH 2-)，2.73(d，1H，J＝17.2Hz，-CH-)，2.04-2.08(m，1H，-CH-)，1.83-1.86(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：172.4，158.4，136.7，134.8，134.2，133.9，133.7，129.4，128.4，127.8，127.7，126.7，124.7，116.0，69.4，57.8，35.4，29.2，24.6。
2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 6g (14.8mmol), lithium aluminum hydride 1.2g (31.6mmol), tetrahydrofuran (THF) 150mL, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the solid that added diethyl ether is separated out, filter dry white solid 2-amino-7-[4-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride 4.0g thereof, productive rate 67%;
Mp 258-260 ℃; 1H NMR (400MHz, DMSO) δ: 8.13 (brs, 3H ,-NH 3 +), 7.44-7.46 (m, 2H, 2 *-ArH), 7.31-7.41 (m, 5H, 5 *-ArH), 7.05-7.08 (m, 3H, 3 *-ArH), 6.94-6.98 (m, 2H, 2 *-ArH), 5.54 (s, 1H ,-OH), 5.12 (s, 2H ,-OCH 2-), 3.42 (s, 2H ,-CH 2-), 2.84 (s, 2H ,-CH 2-), 2.75-2.76 (m, 2H ,-CH 2-), 1.89-1.92 (m, 2H ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 158.5,136.7,134.4,134.3,133.7,133.2,129.6,129.3,128.4,127.9,127.8,126.9,124.3,116.1,69.4,62.8,55.6,33.9,27.1,24.3; Mass spectrum ESI-MS:(C 24H 25NO 2S.HCl) (M ++ 1) 177; Infrared spectra IR (KBr) vcm -1: 3383,3032,2926,2542,1595,1491,1456,1242,1171,1066,1024,827,735,696.
The method for splitting of FC-042 is as follows:
Figure G2008100516876D0000671
Experimentation is with the method for splitting of 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate, get racemic mixture [(±) FC-041] 3g (7.7mmol), S-(+)-amygdalic acid 1.4g (9.2mmol), methyl alcohol 20mL, get levorotatory compound [(-)-FC-042] 0.5g, [α] D 20=-5.0 ° (c=2.16, methyl alcohol) and dextrorotatory compound [(+)-FC-042] 0.4g, [α] D 20=+5.1 ° (c=1.74, methyl alcohol).
Embodiment 22:
The synthetic method of 2-amino-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-043) and hydrochloride (FC-044) (hereinafter to be referred as FC-043, FC-044) thereof is as follows:
Figure G2008100516876D0000681
Synthesizing of 2-(1, the 3-dioxolane)-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-naphthalene
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, between getting-and methoxyphenol 9.3g (74.6mmol), 2-(1, the 3-dioxolane)-7-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.3mmol), salt of wormwood 20g (149.2mmol), Red copper oxide 11.9g (74.6mmol), pyridine 200mL gets faint yellow oily compound 2-(1, the 3-dioxolane)-and 7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-naphthalene 8.5g, productive rate 73%;
1H?NMR(400MHz，CDCl 3)δ：7.20(t，1H，J＝8.4Hz，-ArH)，7.10(d，1H，J＝8.4Hz，-ArH)，6.82(dd，1H，J＝8.4Hz，J＝2.4Hz，-ArH)，6.73(d，1H，J＝2.0Hz，-ArH)，6.63(dd，1H，J＝8.0Hz，J＝1.6Hz，-ArH)，6.56-6.58(m，2H，2×-ArH)，4.03-4.05(m，4H，2×-CH 2-)，3.77(s，3H，-OCH 3)，2.96-2.99(m，4H，2×-CH 2-)，1.94(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：160.6，158.5，154.5，135.8，130.1，129.7，129.4，119.2，116.9，110.2，108.2，107.6，104.2，64.1，54.8，38.8，31.5，27.1。
Synthesizing of 7-(3-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-naphthalene 9g (28.8mmol), right-toluenesulphonic acids 3.3g (19.2mmol), acetone 300mL, get white solid compound 7-(3-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline 7g, productive rate 90%;
mp?82-84℃； 1H?NMR(400MHz，CDCl 3)δ：7.22(t，1H，J＝8.0Hz，-ArH)，6.88(dd，1H，J＝8.4Hz，J＝2.4Hz，-ArH)，6.79(d，1H，J＝2.4Hz，-ArH)，6.65(dd，1H，J＝2.0Hz，J＝8.8Hz，-ArH)，6.56-6.58(m，2H，2×-ArH)，3.78(s，3H，-OCH 3)，3.54(s，2H，-CH 2-)，3.04(t，2H，J＝6.8Hz，-CH 2-)，2.56(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：210.0，160.9，158.5，155.8，134.9，131.6，130.1，128.8，118.7，117.5，110.8，108.7，104.8，55.3，44.9，38.3，27.6。3 ', 4 '-dihydro-7 '-(3-methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-(3-methoxyl group phenoxy group)-2-Tetralone an intermediate of Sertraline 7g (26.2mmol), potassium cyanide 2g (31.3mmol), volatile salt 22.6g (235.8mmol), 50% ethanol 180mL, get solid chemical compound 3 ', 4 '-dihydro-7 '-(3-methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7g, productive rate 79%;
mp?320-323℃； 1H?NMR(400MHz，DMSO)δ：10.70(s，1H，-NH-)，8.30(s，1H，-NH-)，7.25(t，1H，J＝8.0Hz，-ArH)，7.14(d，1H，J＝8.0Hz，-ArH)，6.79-6.83(m，2H，2×-ArH)，6.68(dd，1H，J＝8.4Hz，J＝2.0Hz，-ArH)，6.53(t，1H，J＝2.4Hz，-ArH)，6.49(dd，1H，J＝8.4Hz，J＝2.0Hz，-ArH)，3.72(s，3H，-OCH 3)，3.08(d，1H，J＝16.8Hz，-CH-)，2.86-2.89(m，2H，-CH 2-)，2.76(d，1H，J＝16.8Hz，-CH-)，1.92-1.98(m，1H，-CH-)，1.79-1.83(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.1，160.6，158.3，156.3，154.1，134.5，130.4，130.3，130.0，119.2，117.1，109.9，108.6，104.2，60.5，55.2，36.8，30.1，24.1。
Synthesizing of 2-urea groups-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-urea groups-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-(3-methoxyl group phenoxy group)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7g (20.7mmol), sodium hydroxide 20g (500mmol), water 200mL, get white solid compound 2-urea groups-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 5.6g, productive rate 76%;
mp?309-311℃； 1H?NMR(400MHz，DMSO)δ：12.2(brs，1H，-COOH)，7.25(t，1H，J＝8.0Hz，-ArH.)，7.09(d，1H，J＝8.8Hz，-ArH.)，6.77(s，2H，2×-ArH.)，6.68(d，1H，J＝8.0Hz，-ArH)，6.49-6.53(m，2H，2×-ArH)，6.32(s，1H，-NH-)，5.48(s，2H，-NH 2)，3.73(s，3H，-OCH 3)，3.28(d，1H，J＝16.8Hz，-CH-)，3.14(d，1H，J＝16.8Hz，-CH-)，2.92-2.96(m，2H，-CH 2-)，2.25-2.28(m，1H，-CH-)，1.84-1.92(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：175.9，160.6，158.5，158.2，154.1，136.8，135.8，130.3，129.7，119.3，116.5，110.1，108.6，104.3，56.0，55.2，37.1，29.2，24.3。
Synthesizing of 2-amino-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-6-Oxy-1 in positive heptan, 2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-urea groups-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2g (5.6mmol), lithium aluminum hydride 0.6g (16.8mmol), tetrahydrofuran (THF) 100mL, stirring at room reaction 36h, add 1N NaOH 100mL under the ice bath, ethyl acetate extraction, be spin-dried for solvent and get crude product 2-urea groups-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add 1N NaOH solution 100mL in above-mentioned crude product, heating reflux reaction 8h, cooling, extracted with diethyl ether, be spin-dried for solvent and get crude product 2-amino-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 5mL, 1N hydrochloric acid 0.5mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the adularescent solid that adds diethyl ether is separated out, filter dry white solid 2-amino-7-(3-methoxyl group phenoxy group)-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.5g, the productive rate 26% of getting;
Mp 185-187 ℃; 1H NMR (400MHz, DMSO) δ: 8.19 (brs, 3H ,-NH 3 +), 7.25 (t, 1H, J=8.0Hz ,-ArH.), 7.14 (d, 1H, J=8.0Hz ,-ArH.), 6.79-6.82 (m, 2H, 2 *-ArH), 6.70 (dd, 1H, J=8.0Hz, J=1.2Hz ,-ArH), 6.53 (s, 1H ,-ArH), 6.50 (d, 1H, J=8.0Hz ,-ArH), 5.56 (s, 1H ,-OH), 3.73 (s, 3H ,-OCH 3), 3.44 (d, 2H, J=4.0Hz ,-CH 2-), 2.89 (s, 2H ,-CH 2-), 2.76-2.81 (m, 2H ,-CH 2-), 1.94 (t, 2H, J=6.4Hz ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 106.6,158.1,154.3,134.3,130.4,130.0,129.9,119.2,117.2,110.1,108.7,104.3,62.9,55.6,55.2,34.1,27.4,24.0; Mass spectrum ESI-MS:(C 18H 21NO 3.HCl) (M ++ 1) 299; Infrared spectra IR (KBr) vcm -1: 3387,3018,2926,2632,2542,2010,1603,1489,1265,1153,1136,1043,962,850,771,687.
Embodiment 23:
2-amino-7-[3-(benzyloxy) phenoxy group]-1,2,3, the synthetic method of 4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-045) and hydrochloride (FC-046) (hereinafter to be referred as FC-045, FC-046) thereof is as follows:
Figure G2008100516876D0000701
Synthesizing of 3-benzyloxy phenol
Between getting-and hydroxyl phenol 10g (90.9mmol), salt of wormwood 25g (181.0mmol), ethanol 200mL, heating reflux reaction 2h, slowly drip the mixing solutions of bromotoluene 10.3g (60.6mmol) and ethanol 50mL then, drip Bi Jixu heating reflux reaction 1h, cooling, filter, filtrate is spin-dried for 1N hydrochloric acid and transfers to pH＜2, and ethyl acetate extraction, organic layer are spin-dried for silica gel column chromatography (developping agent: ethyl acetate: sherwood oil=1: 5), get oily compound 3-benzyloxy phenol 4.5g, productive rate 37%; 1H NMR (400MHz, CDCl 3) δ: 7.35-7.42 (m, 4H, 4 *-ArH), 7.31-7.33 (m, 1H ,-ArH), 7.12 (t, 1H, J=8.0Hz,-ArH), 6.55 (dd, 1H, J=2.4Hz, J=7.6Hz ,-ArH), 6.47 (t, 1H, J=2.4Hz ,-ArH), 6.41-6.43 (m, 1H ,-ArH), 5.02 (s, 2H ,-CH 2-O-), 5.00 (s, 1H ,-OH); 13C NMR (100MHz, CDCl 3) δ: 159.8,156.5,136.6,130.2,128.5,127.9,127.5,108.2,107.4,102.5,70.0.
2-(1, the 3-dioxolane)-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-naphthalene synthetic
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get 3-benzyloxy phenol 11.0g (55.0mmol), 2-(1, the 3-dioxolane)-7-bromo-1,2,3,4-tetrahydrochysene-naphthalene 10g (37.3mmol), salt of wormwood 15g (108.7mmol), Red copper oxide 8.0g (55.6mmol), pyridine 250mL gets faint yellow oily compound 2-(1, the 3-dioxolane)-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-naphthalene 10g, productive rate 70%;
1H?NMR(400MHz，CDCl 3)δ：7.28-7.42(m，5H，5×-ArH)，7.19(t，1H，J＝10.8Hz，-ArH)，7.07(d，1H，J＝10.0Hz，-ArH)，6.79(dd，1H，J＝3.2Hz，J＝11.0Hz，-ArH)，6.67-6.71(m，2H，2×-ArH)，6.56-6.63(m，2H，2×-ArH)，5.02(s，2H，-CH 2-O-)，4.03(s，4H，2×-CH 2-)，2.94-2.98(m，4H，2×-CH 2-)，1.96(t，2H，J＝8.0Hz，-CH 2-)； 13CNMR(100MHz，CDCl 3)δ：159.9，158.7，154.4，136.5，135.6，130.3，129.8，129.4，128.7，128.2，127.6，127.2，119.4，117.1，110.6，108.9，107.7，69.6，64.1，38.9，31.6，27.3。
7-[3-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline synthetic
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-naphthalene 10g (25.8mmol), right-toluenesulphonic acids 3.0g (17.2mmol), acetone 200mL, get faint yellow solid compound 7-[3-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline 6.0g, productive rate 68%;
mp?121-123℃； 1H?NMR(400MHz，CDCl 3)δ：7.35-7.45(m，5H，5×-ArH)，7.27(d，1H，J＝8.0Hz，-ArH)，7.23-7.26(m，1H，-ArH)，6.91(dd，1H，J＝8.4Hz，J＝2.4Hz，-ArH)，6.82(s，1H，-ArH)，6.76(dd，1H，J＝8.4Hz，J＝2.0Hz，-ArH)，6.63-6.67(m，2H，2×ArH)，5.05(s，2H，-CH 2-O-)，3.56(s，2H，-CH 2-)，3.07(t，2H，J＝6.8Hz，-CH 2-)，2.59(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：209.7，159.9，158.4，155.5，136.5，134.8，131.6，130.0，128.7，128.4，127.8，127.3，118.7，117.5，110.9，109.3，105.4，69.9，44.8，38.1，27.5。
3 ', 4 '-dihydro-7 '-[3-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-[3-(benzyloxy) phenoxy group]-2-Tetralone an intermediate of Sertraline 5.5g (16.0mmol), potassium cyanide 1.3g (20.0mmol), volatile salt 13.8g (143.75mmol), 50% ethanol 110mL, get white solid compound 3 ', 4 '-dihydro-7 '-[3-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 4.0g, productive rate 63%;
mp?353-355℃； 1H?NMR(400MHz，DMSO)δ：10.25(brs，1H，-NH-)，8.25(s，1H，-NH-)，7.32-7.43(m，5H，5×-ArH)，7.25(t，1H，J＝8.0Hz，-ArH)，7.14(d，1H，J＝8.4Hz，-ArH)，6.75-6.82(m，3H，3×ArH)，6.58(s，1H，-ArH)，6.51(dd，1H，J＝2.0Hz，J＝8.0Hz，-ArH)，5.07(s，2H，-CH 2-O-)，3.07(d，1H，J＝16.8Hz，-CH-)，2.87-2.89(m，2H，-CH 2-)，2.74(d，1H，J＝16.8Hz，-CH-)，1.90-1.96(m，1H，-CH-)，1.78-1.82(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.5，159.7，158.4，156.8，153.9，136.8，134.6，130.4，130.0，128.4，127.8，127.7，119.3，117.3，110.2，109.4，104.9，69.4，60.6，36.9，30.2，24.2。
2-amino-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthoic acid synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-[3-(benzyloxy) phenoxy group]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 4.0g (10.0mmol), sodium hydroxide 10.0g (250mmol), water 100mL, white solid compound 2-amino-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 3.0g, productive rate 77%;
mp?340-343℃； 1H?NMR(400MHz，DMSO)δ：7.32-7.43(m，5H，5×-ArH)，7.25(t，1H，J＝8.0Hz，-ArH)，7.11(d，1H，J＝8.8Hz，-ArH)，6.75-6.79(m，3H，3×ArH)，6.59(s，1H，-ArH)，6.51(d，1H，J＝7.6Hz，-ArH)，5.07(s，2H，-CH 2-O-)，6.28(d，1H，J＝17.2Hz，-CH-)，2.84(d，1H，J＝17.2Hz，-CH-)，2.77-2.79(m，2H，-CH 2-)，2.08-2.14(m，1H，-CH-)，1.94-1.97(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：172.5，159.7，158.4，150.1，136.8，134.9，130.4，130.3，129.9，128.4，127.8，127.7，119.1，116.9，110.3，109.4，105.0，69.4，57.6，35.2，29.2，24.2。
2-amino-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride FC-045046 thereof synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (5.1mmol), lithium aluminum hydride 0.59g (15.3mmol), tetrahydrofuran (THF) 50mL, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol FC-045, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the solid that added diethyl ether is separated out, filter dry white solid 2-amino-7-[3-(benzyloxy) phenoxy group]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride FC-046 0.45g thereof, productive rate 25%;
Mp 236-238 ℃; 1H NMR (400MHz, DMSO) δ: 8.19 (brs, 3H ,-NH 3 +), 7.33-7.43 (m, 5H, 5 *-ArH), 7.26 (t, 1H, J=8.0Hz ,-ArH), 7.13 (d, 1H, J=8.0Hz ,-ArH), 6.76-6.82 (m, 3H, 3 * ArH), 6.59 (s, 1H ,-ArH), 6.52-6.56 (m, 1H ,-ArH), 5.58 (s, 1H ,-OH), 5.07 (s, 2H ,-CH 2-O-), 3.45 (s, 2H ,-CH 2-), 2.89 (s, 2H ,-CH 2-), 2.77-2.79 (m, 2H ,-CH 2-), 1.94 (t, 2H, J=6.8Hz ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 159.7,158.2,154.2,136.8,134.4,130.5,130.0,128.4,127.9,127.7,119.3,117.3,110.3,109.5,105.1,69.3,62.9,55.6,34.1,27.3,24.1; Mass spectrum ESI-MS:(C 24H 25NO 3.HCl) (M ++ 1) 375; Infrared spectra IR (KBr) vcm -1: 3406,3178,3026,2928,2656,2548,2040,1589,1497,1265,1230,1153,1061,953,769,742,683.
Embodiment 24:
2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3, the synthetic method of 4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-047) and hydrochloride (FC-048) (hereinafter to be referred as FC-047, FC-048) thereof is as follows:
2-(1, the 3-dioxolane)-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-naphthalene synthetic
The same 2-(1 of experimentation, the 3-dioxolane)-6-phenoxy group-1,2,3,4-tetrahydrochysene-naphthalene, get a benzyloxy thiophenol 10g (46.3mmol), 2-(1, the 3-dioxolane)-7-bromo-1,2,3,4-tetrahydrochysene-naphthalene 14.2g (52.8mmol), salt of wormwood 23g (166.7mmol), Red copper oxide 16g (111.9mmol), DMF 150mL gets oily compound 2-(1, the 3-dioxolane)-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-naphthalene 14g, productive rate 75%;
1H?NMR(400MHz，CDCl 3)δ：7.30-7.40(m，5H，5×-ArH)，7.13-7.19(m，3H，3×-ArH)，7.08(d，1H，J＝7.6Hz，-ArH)，6.87-6.90(m，2H，2×-ArH)，6.79-6.81(m，1H，-ArH)，5.00(s，2H，-CH 2-)，4.03(t，4H，J＝1.2Hz，2×-CH 2-)，2.93-2.99(m，4H，2×-CH 2-)，1.93-1.98(m，2H，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：158.9，138.2，136.5，135.6，135.0，132.9，130.9，129.9，129.6，129.2，128.2，127.6，127.2，121.8，115.6，112.7，107.6，69.6，64.2，38.7，31.4，27.5。
7-[3-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline synthetic
Experimentation is with 6-phenoxy group-2-Tetralone an intermediate of Sertraline, get 2-(1, the 3-dioxolane)-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-naphthalene 14g (34.6mmol), right-toluenesulphonic acids 4.4g (23.2mmol), acetone 200mL, get faint yellow solid compound 7-[3-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline 8g, productive rate 64%;
mp?186-189℃； 1H?NMR(400MHz，CDCl 3)δ：7.33-7.40(m，5H，5×-ArH)，7.16-7.26(m，4H，4×-ArH)，6.90-6.92(m，2H，2×-ArH)，6.84-6.85(m，1H，-ArH)，5.01(s，2H，-CH 2-)，3.53(s，2H，-CH 2-)，3.05(t，2H，J＝6.8Hz，-CH 2-)，2.56(t，2H，J＝6.8Hz，-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：209.5，159.0，137.4，136.4，136.0，134.4，133.0，131.3，130.2，129.8，128.4，127.8，127.3，122.6，116.4，113.2，69.8，44.6，37.7，27.8。
3 ', 4 '-dihydro-7 '-[3-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone is got 7-[3-(benzyloxy) thiophenyl]-2-Tetralone an intermediate of Sertraline 10g (27.8mmol), potassium cyanide 2.25g (34.6mmol), volatile salt 25g (260.4mmol), water 50mL, ethanol 150mL gets white solid compound 3 ', 4 '-dihydro-7 '-[3-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 8g, productive rate 67%;
mp?373-376℃； 1H?NMR(400MHz，DMSO)δ：10.3(s，1H，-NH-)，8.22(s，1H，-NH-)，7.41-7.30(m，5H，5×-ArH)，7.24(t，1H，J＝7.6Hz，-ArH)，7.13-7.18(m，3H，3×-ArH)，6.89-6.91(m，1H，-ArH)，6.83(s，1H，-ArH)，6.80(t，1H，J＝8.4Hz，-ArH)，5.07(s，2H，-CH 2-)，3.08(d，1H，J＝17.2Hz，-CH-)，2.89-3.07(m，2H，-CH 2-)，2.76(d，1H，J＝17.2Hz，-CH-)，1.92-1.98(m，1H，-CH-)，1.80-1.84(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：178.2，158.8，156.5，137.6，136.7，135.4，134.4，132.9，130.2，130.1，129.9，128.4，127.8，127.7，121.4，115.4，113.0，69.2，60.2，36.6，29.8，24.5。
2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-[3-(benzyloxy) thiophenyl]-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 7.0g (16.3mmol), sodium hydroxide 10g (250mmol), water 100mL, DMSO 100mL, white solid compound 2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 6.5g, productive rate 87%;
mp?353-356℃； 1H?NMR(400MHz，DMSO)δ：7.32-7.41(m，5H，5×-ArH)，7.24(t，1H，J＝7.6Hz，-ArH)，7.19(s，1H，-ArH)，7.13(s，2H，2×-ArH)，6.88-6.90(m，1H，-ArH)，6.83(s，1H，-ArH)，6.80(t，1H，J＝8.4Hz，-ArH)，5.06(s，2H，-CH 2-)，3.28(d，1H，J＝17.2Hz，-CH-)，2.88(d，1H，J＝17.2Hz，-CH-)，2.81-2.85(m，2H，-CH 2-)，2.08-2.16(m，1H，-CH-)，1.95-1.99(m，1H，-CH-)； 13C?NMR(100MHz，DMSO)δ：172.3，158.8，137.5，136.7，135.23，134.7，132.4，130.2，130.1，129.7，128.4，127.8，127.7，121.5，115.5，113.1，69.3，57.5，34.9，28.9，24.6。
2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol synthetic
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthoic acid 6g (14.8mmol), lithium aluminum hydride 1.2g (31.6mmol), tetrahydrofuran (THF) 150mL, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the solid that added diethyl ether is separated out, filter dry white solid 2-amino-7-[3-(benzyloxy) thiophenyl]-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 4g, productive rate 67%;
Mp 258-260 ℃; 1H NMR (400MHz, DMSO) δ: 8.18 (brs, 3H ,-NH 3 +), 7.32-7.40 (m, 5H, 5 *-ArH), 7.26 (t, 1H, J=7.6Hz ,-ArH), 7.13-7.18 (m, 3H, 3 *-ArH), 6.90-6.92 (m, 1H ,-ArH), 6.83 (s, 1H ,-ArH), 6.80 (d, 1H, J=8.0Hz ,-ArH), 5.56 (s, 1H ,-OH), 5.01 (s, 2H ,-CH 2-), 3.43 (s, 2H ,-CH 2-), 2.89 (s, 2H ,-CH 2-), 2.79-2.84 (m, 2H ,-CH 2-), 1.94 (t, 2H, J=6.4Hz ,-CH 2-); 13C NMR (100MHz, DMSO) δ: 158.8,137.2,136.7,134.9,134.1,132.7,130.5,130.3130.1,129.8,128.4,127.8,127.7,121.7,115.6,113.2,69.3,62.8,55.6,33.8,27.1,24.3; Mass spectrum ESI-MS:(C 24H 25NO 2S.HCl) (M ++ 1) 177; Infrared spectra IR (KBr) vcm -1: 3406,3292,3026,2918,2640,2542,2362,1589,1508,1475,1282,1242,1049,771,694.
The method for splitting of FC-047 is as follows:
Figure G2008100516876D0000761
Experimentation is with the method for splitting of 2-amino-7-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate, get racemic mixture [(±) FC-047] 3g (7.7mmol), S-(+)-amygdalic acid 1.4g (9.2mmol), methyl alcohol 20mL, get levorotatory compound [(-)-FC-048] 0.5g, [α] D 20=-5.0 ° (c=2.16, methyl alcohol) and dextrorotatory compound [(+)-FC-048] 0.4g, [α] D 20=+5.1 ° (c=1.74, methyl alcohol).
Embodiment 25:
The synthetic method of 2-amino-7-n-hexyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-049) and hydrochloride (FC-050) (hereinafter to be referred as FC-049, FC-050) thereof is as follows:
Figure G2008100516876D0000762
Synthesizing of 7-n-hexyl-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-normal-butyl-2-Tetralone an intermediate of Sertraline, get 7-bromo-2-Tetralone an intermediate of Sertraline 5g (22.2mmol), normal hexane ylboronic acid 4g (31.6mmol), three water potassiumphosphate 21g (78.9mmol), thricyclohexyl phosphorus 0.7g (2.5mmol), palladium 0.25g (1.1mmol), toluene 100mL, water 5mL gets faint yellow solid compound 7-n-hexyl-2-Tetralone an intermediate of Sertraline 4.5g, productive rate 78%;
mp?80-82℃； 1H?NMR(400MHz，CDCl 3)δ：7.14(d，1H，J＝8.0Hz，-ArH)，7.03(d，1H，J＝8.0Hz，-ArH)，6.94(s，1H，-ArH)，3.56(s，2H，-CH 2-)，3.03(t，2H，J＝6.4Hz，-CH 2-)，2.53-2.59(m，4H，2×-CH 2-)，1.57-1.61(m，2H，-CH 2-)，1.30-1.35(m，6H，3×-CH 2-)，0.89(t，3H，J＝6.8Hz，-CH 3)； 13C?NMR(100MHz，CDCl 3)δ：210.3，141.3，133.6，132.9，127.9，127.2，126.6，44.8，38.1，37.9，35.3，31.5，31.3，28.8，27.7，22.5，22.4，22.1，13.9。
3 ', 4 '-dihydro-7 '-n-hexyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 7-n-hexyl-2-Tetralone an intermediate of Sertraline 5g (21.7mmol), potassium cyanide 1.7g (26.1mmol), volatile salt 19g (198mmol), 50% ethanol 140mL, get white solid compound 3 ', 4 '-dihydro-7 '-n-hexyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 4g, productive rate 62%;
mp?245-248℃； 1H?NMR(400MHz，DMSO)δ：10.7(s，1H，-NH-)，8.28(s，1H，-NH-)，7.02(d，1H，J＝8.0Hz，-ArH)，6.94(d，1H，J＝8.0Hz，-ArH)，6.90(s，1H，-ArH)，3.07(d，1H，J＝17.2Hz，-CH-)，2.80-2.88(m，2H，-CH 2-)，2.72(d，1H，J＝16.8Hz，-CH-)，2.47-2.51(m，2H，-CH 2-)，1.88-1.96(m，1H，-CH-)，1.77-1.80(m，1H，-CH-)，1.49-1.53(m，2H，-CH 2-)，1.26-1.27(m，6H，3×-CH 2-)，0.82-0.87(m，3H，-CH 3)； 13C?NMR(100MHz，DMSO)δ：178.2，156.3，139.8，132.3，131.9，128.6，128.4，126.0，60.8，36.8，34.8，31.1，31.0，30.2，28.4，24.3，22.0，13.9。
Synthesizing of 2-amino-7-n-hexyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid, get 3 ', 4 '-dihydro-7 '-n-hexyl-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 5.0g (16.7mmol), sodium hydroxide 10g (250mmol), water 100mL, get white solid compound 2-amino-7-n-hexyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 4.5g, productive rate 80%;
mp?285-288℃； 1H?NMR(400MHz，DMSO)δ：7.02(d，1H，J＝8.0Hz，-ArH)，6.96(d，1H，J＝8.0Hz，-ArH)，6.93(s，1H，-ArH)，3.26(d，1H，J＝16.8Hz，-CH-)，6.96(d，1H，J＝16.8Hz，-CH-)，2.74-2.84(m，2H，-CH 2-)，2.49(s，2H，-CH 2-)，2.07-2.18(m，2H，-CH 2-)，1.52(s，2H，-CH 2-)，1.27(s，6H，3×-CH 2-)，0.85(s，3H，-CH 3)； 13C?NMR(100MHz，DMSO)δ：172.3，139.2，131.9，131.5，127.6，127.2，125.1，57.1，35.5，34.0，30.2，29.7，29.4，27.5，24.0，20.9，12.7。
Synthesizing of 2-amino-7-n-hexyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-7-n-hexyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid 1.0g (3.6mmol), lithium aluminum hydride 0.4g (10.9mmol), tetrahydrofuran (THF) 20mL, stirring at room reaction 12h adds water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-7-n-hexyl-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, and the solid that added diethyl ether is separated out, and filters, dry white solid 2-amino-7-n-hexyl-1,2,3,4-tetrahydrochysene-2-naphthalene methylate hydrochlorate 0.45g, the productive rate 50% of getting;
Mp 193-195 ℃; 1H NMR (400MHz, DMSO) δ: 8.19 (s, 1H ,-NH 3 +), 7.00 (d, 1H, J=7.6Hz ,-ArH), 6.94 (d, 1H, J=7.6Hz ,-ArH), 6.90 (s, 1H ,-ArH), 5.52 (s, 1H ,-OH), 3.43 (s, 2H ,-CH 2-), 2.83-2.93 (m, 2H ,-CH 2-), 2.69-2.80 (m, 2H ,-CH 2-), 2.47-2.50 (m, 2H ,-CH 2-), 1.90-1.96 (m, 2H ,-CH 2-), 1.50-1.54 (m, 2H ,-CH 2-), 1.25-1.26 (m, 6H, 3 *-CH 2-), 0.83-0.86 (m, 3H ,-CH 3); 13CNMR (100MHz, DMSO) δ: 139.9,132.1,131.6,128.8,128.4,126.2,62.8,55.8,34.7,34.1,31.0,30.9,28.3,27.4,24.3,22.0,13; Mass spectrum ESI-MS:(C 17H 27NO.HCl) (M ++ 1) 269; Infrared spectra IR (KBr) vcm -1: 3431,3275,2960,2922,2852,2619,2536,1948,1583,1497,1466,1439,1066,818.
Embodiment 26:
The synthetic method of 2-amino-6-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol (FC-051) and hydrochloride (FC-052) (hereinafter to be referred as FC-051, FC-052) thereof is as follows:
Synthesizing of 6-(6-methoxyl group hexyl)-2-Tetralone an intermediate of Sertraline
Experimentation is with 7-normal-butyl-2-Tetralone an intermediate of Sertraline, get 6-methoxyl group hexyl boric acid 5g (31.3mmol), (FC-021A) 5g (22.3mmol), three water potassiumphosphate 21g (78.9mmol), palladium 0.25g (1.1mmol), thricyclohexyl phosphorus 0.7g (2.5mmol), toluene 100mL, water 5mL gets yellow oily compound 6-(6-methoxyl group hexyl)-2-Tetralone an intermediate of Sertraline 4.0g, productive rate 69%;
1H?NMR(400MHz，CDCl 3)δ：7.03-7.09(m，3H，3×-ArH)，3.55(s，2H，-CH 2-)，3.36-3.39(m，2H，O-CH 2-)，3.34(s，3H，O-CH 3)，3.03(t，2H，J＝6.8Hz，-CH 2-)，2.59(t，2H，J＝8.0Hz，-CH 2-)，2.55(t，2H，J＝6.8Hz，-CH 2-)，1.55-1.66(m，4H，2×-CH 2-)，1.36-1.39(m，4H，2×-CH 2-)； 13C?NMR(100MHz，CDCl 3)δ：210.4，141.2，136.3，130.2，127.8，127.4，126.7，72.6，58.3，44.4，38.0，35.3，31.3，29.4，28.9，28.2，25.8。
3 ', 4 '-dihydro-6 '-(6-methoxyl group hexyl)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone synthetic
Experimentation is with 3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone, get 6-(6-methoxyl group hexyl)-2-Tetralone an intermediate of Sertraline 5g (19.2mmol), potassium cyanide 1.5g (23.1mmol), volatile salt 17g (177.1mmol), 50% ethanol 140mL, get white solid compound 3 ', 4 '-dihydro-6 '-(6-methoxyl group hexyl)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 3.0g, productive rate 48%;
mp?298-303℃； 1H?NMR(400MHz，DMSO)δ：6.93-6.99(m，3H，3×-ArH)，3.27-3.37(m，2H，O-CH 2-)，3.32(s，3H，O-CH 3)，3.03(d，1H，J＝16.8Hz，-CH-)，2.82-2.92(m，2H，-CH 2-)，2.72(d，1H，J＝16.8Hz，-CH-)，2.47-2.52(m，2H，，-CH 2-)，1.89-1.96(m，1H，-CH-)，1.77-1.80(m，1H，-CH-)1.45-1.55(m，4H，2×-CH 2-)，1.29-1.31(m，4H，2×-CH 2-)； 13C?NMR(100MHz，DMSO)δ：178.3，139.9，134.6，129.8，128.8，128.4，126.0，71.9，60.9，57.8，36.6，34.8，31.0，30.1，29.0，28.6，25.5，24.7。
Synthesizing of 2-amino-6-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthoic acid
Experimentation together, get 3 ', 4 '-dihydro-6 '-(6-methoxyl group hexyl)-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,5-diketone 3.0g (9.0mmol), sodium hydroxide 10g (250mmol), water 100mL, get white solid compound 2-amino-6-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.2g, productive rate 79%;
mp?282-285℃； 1H?NMR(400MHz，DMSO)δ：6.95(m，3H，3×-ArH)，3.28(t，2H，J＝6.4Hz，O-CH 2-)，3.19(s，3H，O-CH 3)，2.88(d，1H，J＝16.8Hz，-CH-)，2.77(s，2H，-CH 2-)，2.47-2.49(m，3H，-CH-，-CH 2-)，2.09-2.13(m，1H，-CH-)，1.97-2.01(m，1H，-CH-)，1.47-1.53(m，4H，2×-CH 2-)，1.29(s，4H，2×-CH 2-)； 13C?NMR(100MHz，DMSO)δ：172.6，139.7，134.3，129.9，128.6，128.2，125.9，71.8，57.7，34.7，30.9，28.9，28.5，25.5，24.8。
Synthesizing of 2-amino-6-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof
Experimentation is with 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride thereof, get 2-amino-6-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthoic acid 2.0g (6.5mmol), lithium aluminum hydride 0.75g (19.7mmol), tetrahydrofuran (THF) 50mL, stirring at room reaction 12h adds water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product 2-amino-6-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product directly carries out next step reaction without separating.Add methyl alcohol 3mL, concentrated hydrochloric acid 0.1mL is in above-mentioned crude product, and stirring at room is reacted 0.5h, the solid that added diethyl ether is separated out, filter dry white solid 2-amino-6-(6-methoxyl group hexyl)-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol and hydrochloride 0.75g thereof, the productive rate 36% of getting;
Mp 208-210 ℃; 1H NMR (400MHz, DMSO) δ: 6.91-6.98 (m, 3H, 3 *-ArH), 5.16 (t, 1H, J=5.2Hz ,-OH), 3.40 (d, 2H, J=5.2Hz ,-CH 2-), 3.26 (t, 2H, J=6.4Hz, O-CH 2-), 3.18 (s, 3H, O-CH 3), 2.84 (s, 2H ,-CH 2-), 2.72-2.80 (m, 2H ,-CH 2-), 2.45-2.49 (m, 2H ,-CH 2-), 1.87-1.91 (m, 2H ,-CH 2-), 1.42-1.54 (m, 4H, 2 *-CH 2-), 1.26-1.28 (m, 4H, 2 *-CH 2-); 13C NMR (100MHz, DMSO) δ: 140.0,134.2,129.6,128.9,128.2,126.1,71.8,62.7,57.7,55.9,34.7,33.7,30.9,28.9,28.5,27.3,25.4,24.7; Mass spectrum ESI-MS:(C 18H 29NO 2.HCl) (M ++ 1) 291; Infrared spectra IR (KBr) vcm -1: 3442,3267,2929,2854,2640,2538,1969,1581,1502,1466,1120,1066,945,820.
Experimental example amino methanol derivant and salt compounds thereof are to the influence of mouse peripheral blood lymphocyte
Experiment material
1, the amino methanol derivant salt compounds is from related embodiment of the present invention, and 15%EDTA, PBS, EP pipe, 15ml centrifuge tube, kapillary, rifle point are available from Shanghai Bioisystech Co., Ltd.The blood cell analytical reagent is available from Shanghai Sysmex company.
2,25 female Babl/c, 20-22g is provided by Jilin University's Experimental Animal Center.
3, automatic hematology analyzer (pocH-100iV Diff) is available from Japan Kobe family Sysmex company
Experimental technique
1, amino methanol derivant salt compounds storage liquid is 20mg/ml.
2, mouse is divided into 5 groups and is respectively control group, the FTY-720 positive controls, low, high dosage experimental group is weighed, is numbered and carry out mark.
2, control group administered physiological saline; The amino methanol derivant salt compounds is low, high dosage dosage experiments group 3mg/kg, 10mg/kg every day twice respectively, abdominal injection.Administration in continuous four days, 3.5h blood sampling after the 4th administration adopts pocH-100 to analyze lymphocyte number.
Experimental result:
Title Molecular weight ??Dose1??mg/kg Inhibiting rate (%) ??Dose2??mg/kg Inhibiting rate (%)
2-amino-1,2,3,4-tetrahydrochysene-2-naphthoic acid ??191.2 ??5 ??15 ??30 ??50
??FC-002 ??177.2 ??5 ??43 ??30 ??55
??FC-004 ??233.3 ??30 ??43 ??60 ??54
2-amino-5-normal-butyl-1,2,3,4-tetrahydrochysene-2-naphthoic acid ??247.3 ??30 ??1 ??60 ??5
??FC-006 ??233.3 ??30 ??1.5 ??60 ??3
??FC-008 ??289.4 ??5 ??28 ??30 ??64
??FC-010 ??291.4 ??5 ??8 ??30 ??24
??FC-012 ??269.3 ??5 ??20 ??30 ??2
??FC-014 ??303.7 ??5 ??1.2 ??30 ??3
??FC-016 ??303.7 ??5 ??2.6 ??30 ??1.1
??FC-018 ??303.7 ??5 ??8 ??30 ??1.8
??FC-020 ??299.3 ??5 ??21 ??30 ??26
Title Molecular weight ??Dose1??mg/kg Inhibiting rate (%) ??Dose2??mg/kg Inhibiting rate (%)
??FC-022 ??375.4 ??5 ??28 ??30 ??29
??FC-024 ??253.3 ??5 ??13 ??30 ??21
??FC-028 ??391.5 ??5 ??40 ??20 ??66
??FC-030 ??2914 ??5 ??25 ??30 ??70
??FC-032 ??269.3 ??5 ??2.5 ??30 ??2.2
??FC-034 ??299.3 ??5 ??0.8 ??30 ??2.3
??FC-038 ??253.3 ??5 ??5 ??30 ??16
??FC-040 ??291.4 ??5 ??12 ??20 ??17
??FC-042 ??391.5 ??5 ??40 ??20 ??64
??FC-044 ??299.3 ??5 ??3 ??30 ??2.8
??FC-046 ??375.4 ??5 ??26 ??30 ??60
??FC-048 ??391.5 ??5 ??28 ??30 ??74
Title Molecular weight ??Dose1??mg/kg Inhibiting rate (%) ??Dose2??mg/kg Inhibiting rate (%)
??FC-050 ??261.4 ??5 ??12 ??20 ??54
??FC-052 ??291.4 ??5 ??3 ??30 ??21
??(-)FC-008 ??289.4 ??5 ??37 ??20 ??79
??(+)FC-028 ??391.5 ??5 ??37 ??30 ??45
??(-)FC-028 ??391.5 ??5 ??19 ??30 ??49
??(+)FC-042 ??391.5 ??5 ??41 ??30 ??20
??(-)FC-042 ??391.5 ??5 ??23 ??30 ??55
??(+)FC-048 ??391.5 ??5 ??14 ??30 ??56
??(-)FC-048 ??391.5 ??5 ??19 ??30 ??67
Annotate: inhibiting rate (%)=(control group-experimental group)/control group * 100%
Data show in the table: the amino methanol derivant salt compounds can reduce mouse peripheral blood lymphocyte number.

Claims (9)

1. amino methanol derivant and salt compounds thereof is characterized in that: formula I compound
Wherein:
X=methylene radical, oxygen;
n＝2；
The R1=methyl, chlorine, bromine, fluorine;
R2=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
R3=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
The R4=methyl, chlorine, bromine, fluorine;
And acceptable salt on the physiology.
2. amino methanol derivant as claimed in claim 1 and salt compounds thereof is characterized in that, formula II compound:
Figure F2008100516876C0000021
Wherein:
The R1=methyl, chlorine, bromine, fluorine;
R2=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
R3=H, C 4-C 6-C 8Alkyl, heptan the oxygen base, phenoxy group, 4-methoxyl group phenoxy group, 4-(benzyloxy) phenoxy group, phenyl, 6-methoxyl group hexyl, 4-(benzyloxy) thiophenyl, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, 3-(benzyloxy) thiophenyl, halogen, 6-methoxyl group hexyl, phenoxy group, the 2-chlorophenoxy, the 3-chlorophenoxy, the 4-chlorophenoxy, 3-methoxyl group phenoxy group, 3-(benzyloxy) phenoxy group, phenyl, 3-(benzyloxy) thiophenyl, 6-methoxyl group hexyl;
The R4=methyl, chlorine, bromine, fluorine;
And acceptable salt on the physiology.
3. amino methanol derivant as claimed in claim 2 and salt compounds thereof is characterized in that, are hydrochloride compound.
4. the preparation method of amino methanol derivant as claimed in claim 2 is characterized in that comprising the following steps:
Figure F2008100516876C0000031
Get 1 times of amount of (5,6,7,8 bit strips are substituent)-2-Tetralone an intermediate of Sertraline, 1.1 times of amounts of potassium cyanide, 9 times of amounts of volatile salt, 50% ethanolic soln is an amount of, heating reflux reaction 2h, ethanol steams and removes, and filters, and filter cake is washed to neutrality, dry (5 ', 6 ', 7 ', 8 ' bit strip is substituent)-3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2, the 5-diketone;
Get (5 ', 6 ', 7 ', 8 ' bit strip is substituent)-3 ', 4 '-dihydro-spiral shell [tetrahydroglyoxaline-4,2 ' (1 ' H)-naphthalene]-2,1 times of amount of 5-diketone, alkaline solution is excessive greatly, heating reflux reaction, transfer pH=6 with HCl, filter, the washing filter cake is extremely neutral, dry (5,6,7,8 bit strips are substituent)-2-amino-1,2,3, the 4-tetrahydrochysene-2-naphthoic acid of getting;
Get (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-1 times of amount of 2-naphthoic acid, 3 times of amounts of lithium aluminum hydride, tetrahydrofuran (THF) is an amount of, stirring at room reaction 12h, add water decomposition, ethyl acetate extraction, organic phase be spin-dried for crude product (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol.
5. the preparation method of amino methanol derivant hydrochloride as claimed in claim 2 is characterized in that comprising the following steps:
Figure F2008100516876C0000041
The crude product compound of obtaining (5,6,7,8 bit strips are substituent) 2-amino-1,2,3,4-tetrahydrochysene-2-naphthalene methyl alcohol, this crude product compound directly carries out next step reaction without separating: it is an amount of to add methyl alcohol, concentrated hydrochloric acid is measured in above-mentioned crude product for 1 times, stirring at room reaction 0.5h, the solid that added diethyl ether is separated out, filter dry white solid (5,6,7,8 bit strips are substituent) 2-amino-1,2,3, the 4-tetrahydrochysene-2-naphthalene methylate hydrochlorate of getting.
6. the application in the preparation immunosuppressive drug of amino methanol derivant as claimed in claim 1 and salt compounds thereof.
7. the application in the medicine of preparation treatment graft-rejection of amino methanol derivant as claimed in claim 1 and salt compounds thereof.
8. the application in the medicine of preparation treatment immune inflammation disease of amino methanol derivant as claimed in claim 1 and salt compounds thereof.
9. the application in the medicine of preparation treatment multiple sclerosis, systemic lupus erythematous, rheumatoid arthritis of amino methanol derivant as claimed in claim 1 and salt compounds thereof.
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Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH637363A5 (en) * 1977-11-24 1983-07-29 Sandoz Ag Process for preparing novel 2-aminotetralins
IT1294931B1 (en) * 1997-09-22 1999-04-23 Sigma Tau Ind Farmaceuti DERIVATIVES OF 2-AMINOTETHRALIN PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, ACTIVE IN THE
EP1539674A1 (en) * 2002-09-13 2005-06-15 Novartis AG Amino-propanol derivatives
DE102005014089A1 (en) * 2005-03-22 2006-09-28 Schering Ag Tetrahydronaphthalene derivatives, process for their preparation and their use as anti-inflammatory agents
CN1891212B (en) * 2005-07-07 2010-10-13 马启明 Oral preparation and its preparing method
WO2007092638A1 (en) * 2006-02-09 2007-08-16 University Of Virginia Patent Foundation Bicyclic sphingosine 1-phosphate analogs
JP2010510249A (en) * 2006-11-21 2010-04-02 ユニバーシティ オブ バージニア パテント ファンデーション Sphingosine = 1-tetralin analog having 1-phosphate agonist activity

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